CA3192169A1 - A compound as a thyroid hormone beta receptor agonist and use thereof - Google Patents

A compound as a thyroid hormone beta receptor agonist and use thereof

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Publication number
CA3192169A1
CA3192169A1 CA3192169A CA3192169A CA3192169A1 CA 3192169 A1 CA3192169 A1 CA 3192169A1 CA 3192169 A CA3192169 A CA 3192169A CA 3192169 A CA3192169 A CA 3192169A CA 3192169 A1 CA3192169 A1 CA 3192169A1
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atoms
alkyl
independently
mmol
compound
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Inventor
Jianchao DENG
Yongxiang Li
Haoxiong QIN
Xiaomin Zheng
Jianghong Yu
Zheng Gu
Daoqian CHEN
Huantian ZHAO
Jianhao LI
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Sunshine Lake Pharma Co Ltd
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Sunshine Lake Pharma Co Ltd
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Publication of CA3192169A1 publication Critical patent/CA3192169A1/en
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

Provided are a compound serving as a thyroid hormone ? receptor agonist and uses of the compound, also provided is a pharmaceutical composition comprising the compound. The compound or the pharmaceutical composition is applicable in preparing a medicament for preventing, treating, or alleviating thyroid hormone ? receptor agonist-modulated diseases, and specifically applicable in preparing a medicament for treating nonalcoholic fatty liver disease.

Description

CA Application CPST Ref: 21924/00056
2
3 FIELD OF THE INVENTION
4 [0001] The invention belongs to the pharmaceutical field. It specifically relates to a compound as a thyroid hormone 13 receptor agonist and use thereof, and further relates to a pharmaceutical composition containing the compound. The present invention further relates to the use of the compound and pharmaceutical composition in the manufacture of a medicament for preventing, treating or alleviating diseases regulated by thyroid hormone 13 8 receptors, especially in the manufacture of a medicament for treating non-alcoholic fatty liver disease.

[0002] Thyroid hormone (TH) plays an extremely important role in growth, differentiation, development and maintenance of metabolic balance. TH is synthesized by the thyroid and secreted into the circulatory system in two major forms, triiodothyronine (T3) and tetraiodothyronine (T4). Although T4 is the predominant form secreted 13 by the thyroid, T3 is the more physiologically active form. T4 is converted to T3 by tissue-specific deiodinases, 14 which are present in all tissues but mainly in the liver and kidney.
[0003] The physiological action of TH is mainly carried out through the thyroid hormone receptor (TR). TR
16 is a member of the nuclear receptor superfamily, a transcription factor induced by ligand T3, and plays a central role 17 in mediating the action of ligand T3. TR is mainly located in the nucleus, forms a heterodimer with retinoid X

receptor (RXR) and other nuclear receptors, and binds to the thyroid hormone response element (TRE) in the promoter region of the target gene, thereby regulating gene transcription.
There are two subtypes of TR: TRa and TR13. TRa can be divided into TRal and TRa2, and TR13 can be further divided into TR131 and TR132. Among them, only TRa 1 , TR131 and TR132 can bind to the ligand T3. TRa mainly regulates heart rate, and TR13 plays a key role 22 in controlling hepatic cholesterol metabolism and inhibiting thyroid-stimulating hormone (TSH) release, which may 23 be related to the high expression of TR13 in the liver and pituitary gland.

[0004] TH has some therapeutic benefit if side effects can be minimized or eliminated (Paul M. Yen et. al.
Physiological Reviews, Vol. 81(3): pp. 1097-1126(2001); Paul Webb et. al.
Expert Opin. Investig. Drugs, Vol. 13(5):

pp. 489-500 (2004)). For example, TH increases metabolic rate, oxygen consumption, and heat production, thereby reducing body weight. Reducing body weight will have a beneficial effect on obese patients by improving obesity-related co-morbidities and may also have a beneficial effect on glycemic control in obese patients with type 2 29 diabetes.
[0005] TH also lowers serum low-density lipoprotein (LDL) (Eugene Morkin et.
al. Journal of Molecular and Cellular Cardiology, Vol. 37: pp. 1137-1146 (2004)). Hyperthyroidism has been found to be associated with low total serum cholesterol due to TH increasing hepatic LDL receptor expression and stimulating the metabolism 33 of cholesterol to bile acids (JJ. Abrams et. al. J. Lipid Res., Vol. 22: pp. 323-38 (1981)). Hypothyroidism is associated with hypercholesterolemia, and TH replacement therapy has been reported to lower total cholesterol (M.
Aviram et. al. Clin. Biochem., Vol. 15: pp. 62-66 (1982); JJ. Abrams et. al.
J. Lipid Res., Vol. 22: pp. 323-38 (1981)).
36 In animal models, TH has been shown to have beneficial effects in increasing HDL
cholesterol and increasing the conversion of LDL to HDL by increasing the expression of apo A-1 (one of the main apolipoproteins of HDL) (Gene CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 C. Ness et. al. Biochemical Pharmacology, Vol. 56: pp. 121-129 (1998);
GJ. Grover et. al. Endocrinology, Vol. 145:
2 pp. 1656-1661 (2004); GJ. Grover et. al. Proc. Natl. Acad. Sci. USA, Vol.
100: pp. 10067-10072 (2003)). The 3 incidence of atherosclerotic vascular diseases is directly related to the level of LDL cholesterol. Through the 4 regulation of LDL and HDL, TH may also reduce the risk of atherosclerosis and other cardiovascular diseases.
Additionally, there is evidence that TH reduces lipoprotein(a), an important risk factor that is elevated in
6 atherosclerotic patients (Paul Webb et. al. Expert Opin. Investig. Drugs, Vol. 13(5): pp. 489-500 (2004); de Bruin
7 et. al. J. Clin. Endo. Metab., Vol. 76: pp. 121-126 (1993)).
8 [0006] TH is also a key signal for oligodendrocyte differentiation and myelination during development and
9 stimulates remyelination in adult models of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005).
However, due to the limited therapeutic window to achieve remyelination while avoiding the cardiotoxicity and 11 bone demineralization associated with chronic hyperthyroidism, TH cannot be used in long-term courses. Some TH
12 analogs can activate TH-responsive genes while avoiding TH-related disadvantages by exploiting the molecular and 13 physiological features of TH receptors (Mahn et. al. Mini Rev Med Chem 7:79-86, 2007).
14 [0007] In addition, non-alcoholic fatty liver disease (NAFLD) is also closely related to TH. On the one hand, NAFLD affects the transformation and inactivation of TH, which can lead to a decrease in the level of serum TH;
16 on the other hand, the decrease in the level of TH further causes lipid metabolism disorder and glucose metabolism 17 disorder, and participates in the occurrence of NAFLD. Studies have shown that fatty liver formation in rats was 18 induced by a choline-methionine-deficient diet, and the reversal of fatty liver can be observed after feeding T3 19 (Perra A, et al. Faseb, 2008,22 (8): 2981).
[0008] However, endogenous TH is non-selective and has side effects, such as hyperthyroidism, especially 21 related to cardiovascular toxicity. Therefore, the development of TH
analogues (such as thyroid hormone 13 receptor 22 agonists) that avoid the adverse effects of hyperthyroidism while maintaining the beneficial effects of TH will open 23 new avenues for the treatment of patients with diseases such as obesity, hyperlipidemia, hypercholesterolemia, 24 diabetes, hepatic steatosis, nonalcoholic fatty liver disease, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease, and related conditions and diseases.

27 [0009] The present invention provides a class of compounds with good agonistic activity on thyroid 28 hormone 3 receptors. Such compounds and their pharmaceutical compositions can be used in the manufacture of a 29 medicament for preventing, treating or alleviating nonalcoholic fatty liver diseases, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, 31 hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, 32 glycogen storage disease type 1A, hypothyroidism or thyroid cancer in patients.
33 [0010] In one aspect, the present invention provides a compound having Formula (I) or a stereoisomer, a 34 geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 R3d R3c A
R3a N N R2 R3b 2 wherein, 3 Y is -0-, -S-, -C(=0)-, C1_6 alkylene, C2_6 alkenylene, C2_6 alkynylene, -NR C(=0)- or 4 wherein the Y is optionally substituted with 1, 2 or 3 Rx;
R is H, deuterium, C1-6 alkyl, C1_6 haloalkyl, hydroxy C1-6 alkyl, amino C1-6 alkyl or cyano C1-6 alkyl;
6 each of R3d, R31', R3c and R3d is independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -SH, 7 C1_6 alkyl, C1_6 alkoxy, C1_6 alkylthio, C1_6 alkylamino, C1_6 haloalkyl, C1_6 haloalkoxy, hydroxy C1-6 alkyl, amino 8 C1_6 alkyl or cyano C1_6 alkyl;
9 RI is H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(=0)-C1_6 alkoxy, -C(=0)-C1_6 alkyl, -C(=0)-C1_6 alkylamino, -C(=0)NH2, -S(=0)2-C1_6 alkyl, -S(=0)2-C1-6 11 alkylamino, -S(=0)2N112, C1_6 alkylamino, C1_6 alkoxy, C1_6 haloalkyl, C1-6 haloalkoxy, hydroxy C1-6 alkyl, amino 12 C1-6 alkyl, carboxy C1-6 alkyl or cyano C1-6 alkyl;
13 R2 is H, deuterium, C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, 14 C6-10 aryl or heteroaryl consisting of 5-6 atoms;
Ei ,U1 Z

L3 63 ,5 E61) Z3 ring A is 0 , 0 , 0 or R5 ;
wherein, ring A is 16 optionally substituted with 1, 2 or 3 RY;
17 each of E1, U1 and Z1 is independently -(CR"R')q-, -00)-, -0-, -S-, -S(0)-, -S(=0)2- or -NRa-;
18 each of E2, U2 and Z2 is independently -CR4cR4d-, -C(-0)-, -0-, -S-, -8(-0)-, -S(-0)2- or -NR"-;
19 each of E3, E6, U3 and Z3 is independently -CWeR4f-, -C(-0)-, -0-, -S-, -S(-0)-, -S(-0)2- or -NRc-;
Ect is -CR4g= or -N-; E5 is -CR"- or -N-;
21 qis0,1, 2 or3;
22 each Ra, Rb, RC and R5 is independently H, deuterium, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-23 6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6_10 aryl or heteroaryl consisting of 5-6 atoms, wherein each Ra, 24 RI', Wand R5 is independently and optionally substituted with 1, 2 or 3 WI;
each Wa, R41', R4c, R4d, R4C, R41', R4g and R" is independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -26 OH, -NH2, -SH, C1-6 alkyl, C2_6 alkenyl, C2-6 alkynyl, C1_6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, C1-6 haloalkoxy, 27 C3-6 cycloalkyl, C3-6 cycloalkyl-Ci4. alkylene, heterocyclyl consisting of 5-6 atoms, (heterocyclyl consisting of 5-6 28 atoms)-C14. alkylene, C6-10 aryl, C6_10 aryl-C1_4alkylene, heteroaryl consisting of 5-6 atoms or (heteroaryl consisting 29 of 5-6 atoms)-Ci4. alkylene, wherein each R4a, Rab, Rac, Rad, Rae, Rai., -4g and R' is independently and optionally substituted with 1, 2 or 3 RY2;

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 or R4a and R4b, together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, or 124e and R4d, together with the carbon atoms to which they are attached, form a C3_8 carbon ring or a heterocyclyl consisting of 5-6 atoms, or Wle and R4f, together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3_8 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY3;

each Rx is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C1_6 alkyl, C1_6 haloalkyl, C1_6 haloalkoxy, 7 C1_6 alkoxy or C1_6 alkylamino;

each RY is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C1_6 alkyl, C1_6 haloalkyl, C1_6 haloalkoxy, C1_6 alkoxy or C1_6 alkylamino; or two RY linked on adjacent atoms, together with the atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-8 carbon ring and 11 heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RS;

each RYI is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-C1_6 alkyl, -C(=0)-C1-alkoxy, -C(=0)-C1-6 alkyl, -C(=0)-C1-6 alkylamino, -C(=0)NH2, -S(=0)2-C1-6 alkyl, -S(=0)2-C1-6 alkylamino, -S(=0)2N112, CI-6 alkyl, CI-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkoxy, C1-6 alkylthio, CI-6 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each RYI is optionally 16 substituted with 1, 2 or 3 Rz;

each Rz, RY2, RY3 and RS is independently deuterium, F, Cl, Br, I, -CN, -OH, -NI42, -COOH, C1-6 alkyl, C1-6 18 haloalkyl, C1_6 haloalkoxy, Cis alkoxy, C1-6 alkylthio or C1_6 alkylamino.

[0011] In some embodiments, each of R3a, R31', R3e and R3d is independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl or cyanomethyl.

[0012] In some embodiments, RI is H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NI-12, -SH, methyl, ethyl, n-propyl, isopropyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CCH, -C(=0)-OCH3, -C(=0)-OCH2CH3, -C(=0)-OCH(CH3)2, -C(=0)-OCH2CH2CH3, -C(=0)-0(CH2)3CH3, -C(=0)-OCH2CH(CH3)2, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-NHCH3, -C(=0)-N(CH3)2, -C(=0)NH2, -S(=0)2-CH3, -S(=0)2-CH2CH3, -S(=0)2-NHCH3, -S(=0)2NH2, methylamino, ethylamino, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -27 OCHF2, -OCH2F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

[0013] In some embodiments, each Ra, Rb, Re and R5 is independently H, deuterium, C14 alkyl, C2-4 alkenyl, C2_4 alkynyl, Ci_zt haloalkyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each Ra, R", Re and R5 is optionally substituted with 1,2 or 3 RYI; wherein RYI has the meaning 31 described in the present invention.

[0014] In some embodiments, each Ra, R", Re and R5 is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CCH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein each Ra, Rb, Re and Rd 37 is independently and optionally substituted with 1, 2 or 3 RYI; wherein RY' has the meaning described in the present CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 invention.
2 [0015] In some embodiments, each WI is independently deuterium, F, Cl, Br, I, -CN, -OH, -NT-I2, -SH, oxo, 3 -0C(=0)-C14 alkyl, -C(=0)-C14 alkoxy, -C(=0)-C14 alkyl, -C(=0)-C14 alkylamino, -C(=0)NI-I2, -S(=0)2-C14 4 alkyl, -S(=0)2-C14 alkylamino, -S(=0)2NH2, C14 alkyl, C14 haloalkyl, C14 haloalkoxy, C14 alkoxy, C14 alkylthio, C14 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C640 aryl or heteroaryl consisting of 5-6 6 atoms, wherein each RY1 is independently and optionally substituted with 1, 2 or 3 Rz; wherein Rz has the meaning 7 described in the present invention.
8 [0016] In some embodiments, each RY1 is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, 9 -0C(=0)-methyl, -0C(=0)-ethyl, -0C(=0)-n-propyl, -0C(=0)-isopropyl, -0C(=0)-n-butyl, -0C(=0)-tert-butyl, -OC(=0)-isobutyl, -C(=0)0-methyl, -C(=0)0-ethyl, -C(=0)0-n-propyl, -C(=0)0-isopropyl, -C(=0)0-n-butyl, -11 C(=0)0-tert-butyl, -C(=0)0-isobutyl, -C(=0)-methyl, -C(=0)-ethyl, -C(=0)-n-propyl, -C(=0)-isopropyl, -C
12 (=0)-n-butyl, -C(=0)-tert-butyl, -C(=0)-isobutyl, -C(=0)-methylamino, -C(=0)-ethylamino, -C(=0)NH2, -13 S(=0)2-C1-3 alkyl, -S(=0)2-C1-3 alkylamino, -S(=0)2N112, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -14 CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl, 16 cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, 17 piperidinyl, morpholinyl, thiomoipholinyl, piperazinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, 18 pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each RY1 is independently and optionally substituted 19 with 1, 2 or 3 Rz; wherein Rz has the meaning described in the present invention.
[0017] In some embodiments, each R4a, R4b, R4c, R4d, R4e, R4f, r.4g tk and R4" is independently H, deuterium, 21 F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, 22 -CH2CH=CH2, -CH=CHCH3, -CCH, methoxy, ethoxy, methylamino, ethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, 23 -CH2CHF2, -0CF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, 24 cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomoipholinyl, piperazinyl, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, 26 tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, 27 piperazinyl-CH2-, phenyl, phenyl-CH2-, phenyl-CH2CH2-, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, 28 pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-29 , pyridyl-CH2- or pyrrolyl-CH2-, wherein each R4a, Rib, Rae, R4d, R4e, R4f, Rag and x ,-.4h is independently and optionally substituted with 1, 2 or 3 V;
31 [0018] or R44 and R41', together with the carbon atoms to which they are attached, form a C3-6 carbon ring or 32 a heterocyclyl consisting of 5-6 atoms, or R4c and R4d, together with the carbon atoms to which they are attached, 33 form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, or 124e and R4f, together with the carbon atoms to 34 which they are attached, form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-6 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY3;
36 wherein RY2 and RY3 have the meanings described in the present invention.
37 [0019] In some embodiments, each Rz, RY2, RY3 and RY4 is independently deuterium, F, Cl, Br, I, -CN, -OH, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 -NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -OCH2F, methoxy, ethoxy 2 or methylamino.
3 [0020] In another aspect, the present invention relates to a pharmaceutical composition comprising the 4 compound of the present invention, optionally, further comprising any one of pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles or any combination thereof 6 [0021] In one aspect, the present invention relates to use of the compound of the present invention or the 7 pharmaceutical composition of the present invention in the manufacture of a medicament for stimulating thyroid 8 hormone receptors; or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
9 [0022] In one aspect, the present invention relates to a method of stimulating thyroid hormone receptors, or preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject comprising 11 administering to the subject a therapeutically effective amount of the compound of the present invention or the 12 pharmaceutical composition of the present invention.
13 [0023] In one aspect, the present invention relates to the compound of the present invention or the 14 pharmaceutical composition of the present invention for use in stimulating thyroid hormone receptors; or in preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject.
16 [0024] In some embodiments, the thyroid hormone receptor of the present invention is a thyroid hormone 13 17 receptor.
18 [0025] In some embodiments, the diseases regulated by thyroid hormone receptors in the present invention 19 are neurodegenerative diseases, nonalcoholic fatty liver diseases, idiopathic pulmonary fibrosis (IPF), atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, 21 dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease 22 type 1A, hypothyroidism or thyroid cancer.
23 [0026] In another aspect, the present invention relates to use of the compound of the present invention or 24 the pharmaceutical composition of the present invention in the manufacture of a medicament for preventing, treating or alleviating the following diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, 26 idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, 27 hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism 28 disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
29 [0027] In another aspect, the present invention relates to a method of preventing, treating or alleviating the following diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, idiopathic 31 pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, 32 hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, 33 glycogen storage disease type 1A, hypothyroidism or thyroid cancer in a subject comprising administering to the 34 subject a therapeutically effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.
36 [0028] In another aspect, the present invention relates to the compound of the present invention or the 37 pharmaceutical composition of the present invention for use in preventing, treating or alleviating the following CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, idiopathic pulmonary fibrosis, 2 atherosclerosis, coronary heart diseases, hypertension, hypercholesterol emia, hyper] ipidemia, hypertriglyceridemia, 3 dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease 4 type 1A, hypothyroidism or thyroid cancer.
[0029] In some embodiments, the nonalcoholic fatty liver disease described in the present invention is 6 nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis associated with nonalcoholic 7 fatty liver disease or primary liver cancer.
8 [0030] In some embodiments, the neurodegenerative disease described in the present invention is 9 demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS) or 11 Alzheimer's disease.
12 [0031] The foregoing merely summarizes certain aspects disclosed herein, but is not limited to these aspects.
13 These and other aspects are described more fully below.

[0032] The invention provides a class of compounds with good agonistic activity on thyroid hormone beta 16 receptors, its preparation method, its pharmaceutical composition and its application. Skilled in the art can learn 17 from this article to properly improve the process parameters to implement the preparation method. Of particular 18 note is that all similar substitutions and modifications to the skilled person is obvious, and they are deemed to be 19 included in the present invention.
DEFINITIONS AND GENERAL TERMINOLOGY
21 [0033] Reference will now be made in detail to certain embodiments of the invention, examples of which 22 are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, 23 modifications, and equivalents which may be included within the scope of the present invention. One skilled in the 24 art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials 26 described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs 27 from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or 28 the like, this application controls.
29 [0034] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various 31 features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided 32 separately or in any suitable subcombination.
33 [0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is 34 commonly understood by one skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
36 [0036] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this 37 invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry 2 are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's 3 Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the 4 entire contents of which are hereby incorporated by reference.
[0037] The grammatical articles "a", "an" and "the", as used herein, are intended to include "at least one"
6 or "one or more" unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used 7 herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article. By way of example, 8 "a component" means one or more components, and thus, possibly, more than one component is contemplated and 9 may be employed or used in an implementation of the described embodiments.
[0038] Unless otherwise stated, terms used in the present invention in the specification and claims have the 11 following definitions.
12 [0039] The term "comprise" is an open expression, it means comprising the contents disclosed herein, but 13 don't exclude other contents.
14 [0040] As described herein, compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species 16 of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the 17 phrase "substituted or unsubstituted". The term "optionally" means that the subsequently described event or 18 circumstance can but need not occur, and the description includes instances where the event or circumstance occurs 19 and instances where the event or circumstance does not occur. In general, unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position 21 in a given structure can be substituted with more than one substituent selected from a specified group, the substituent 22 may be either the same or different at each position. The substituents described therein can be, but are not limited 23 to, H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, alkyl, alkoxy, alkylthio, alkylamino, haloalkyl, 24 haloalkoxy, hydroxyalkyl, aminoalkyl, cyanoalkyl, carboxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkylene, heterocyclyl-alkylene, carbocyclyl, heterocyclyl, aryl, aryl-alkylene, heteroaryl, heteroaryl-alkylene, and the like.
26 [0041] Furthermore, what need to be explained is that the phrase "each..
.is independently" and "each 27 of...and...is independently", unless otherwise stated, should be broadly understood. The specific options expressed 28 by the same symbol are independent of each other in different groups; or the specific options expressed by the same 29 symbol are independent of each other in same groups.
[0042] At various places in the present specification, substituents of compounds disclosed herein are 31 disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual 32 subcombination of the members of such groups and ranges. For example, the term "CI-6 alkyl" specifically refers to 33 independently disclosed CI alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, Czt alkyl, C5 alkyl and C6 alkyl; "C3_8 34 cycloalkyl" especially refers to independently disclosed C3 cycloalkyl, Czt cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl and C8 cycloalkyl; "heterocyclyl consisting of 3-6 atoms" refers to heterocyclyl consisting of 3 atoms, 36 heterocyclyl consisting of 4 atoms, heterocyclyl consisting of 5 atoms and heterocyclyl consisting of 6 atoms.
37 [0043] At various places in the present specification, linking substituents are described. Where the structure CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it is understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0044] The term "alkylene" refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms.
Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms, i.e., C1_6 alkylene; in some embodiments, the alkylene group contains 1-4 carbon atoms, i.e., C1-4 alkylene; such examples include, but are not limited to, methylene (-CH2-), ethylene (including -CH2CH2- or -CH(CH3)-), isopropylidene (including -CH(CH3)CH2- or -C(CH3)2-), n-propylene (including -CH2CH2CH2-, -CH(CH2CH3)- or -CH2CH(CH3)-), and the like. Wherein, the alkylene group may be optionally substituted with one or more 11 substituents disclosed herein.

[0045] The term "alkyl" or "alkyl group" refers to a saturated linear or branched-chain monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group is optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-
10 carbon atoms; in other embodiments, the alkyl group contains 1-8 carbon atoms, i.e., C1-8 alkyl; in still other embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C1-6 alkyl; in yet other embodiments, the alkyl group contains 1-4 carbon atoms, 17 Le., C1-4 alkyl.

[0046] Examples of alkyl group include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2C113), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(C113)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(C112C113)2), 2-methyl-2-butyl (-C(CH3)2C112C113), 3-methyl-2-butyl (-CH(CH3)CH (CH3)2), 3-methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1 -butyl (-CH2CH(CH3)CH2CH3), 23 n-heptyl, n-octyl, etc.

[0047] The term "alkenyl" refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon 5p2 double bond, wherein the alkenyl radical may be optionally substituted with one or more substituents described herein, including radicals having "cis" and "trans" orientations, or alternatively, "E- and "Z" orientations. In some embodiments, the alkenyl contains 2-8 carbon atoms; in other embodiments, the alkenyl contains 2-6 carbon atoms, i.e., C2-6 alkenyl; in still other 29 embodiments, the alkenyl contains 2-4 carbon atoms, i.e., C2_4 alkenyl.
[0048] Examples of alkenyl group include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), 31 propenyl (-CH=CHCH3), butenyl (-CH=CHCH2CH3, -CH2CH=CHCH3, -CH2CH2CH=CH2, -CH=C(CH3)2, -32 CH=C(CH3)2, -CH2C(CH3)=CH2), pentenyl (-CH2CH2CH2CH=CH2, -CH2CH2CH=CHCH3, -CH2CH2CH=CHCH3, -CH2CH=CHCH2CH3, -CH=CHCH2CH2CH3, -CH2CH2C(CH3)=CH2, -CH2CH=C(CH3)2, -34 CH=CHCH(CH3)2, -C(CH2CH3)=CHCH3, -CH(CH2CH3)CH=CH2), and so on.
[0049] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, wherein at least one unsaturated site is a carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents described herein. In some embodiments, the alkynyl contains CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 2-8 carbon atoms; in other embodiments, the alkynyl contains 2-6 carbon atoms, i.e., C2_6 alkynyl; in still other 2 embodiments, the alkynyl contains 2-4 carbon atoms, i.e., C24 alkynyl.
Some non-limiting examples of the alkynyl 3 group include ethynyl (-CCH), 1-propynyl (-CCH-CH3), propargyl (-CJ2CCH), 1-butynyl, 2-butynyl, 1-4 pentynyl, 2-pentynyl, 3-methyl- 1 -butynyl, 1-hexynyl, 1-heptynyl and 1-octynyl, etc.
[0050] The term "alkoxy" refers to an alkyl group, attached to the parent molecular moiety via an oxygen 6 atom, i.e., -0-alkyl, wherein the alkyl group has the meaning as described in the present invention, wherein the 7 alkoxy group can be optionally substituted by one or more substituents described in the present invention. In some 8 embodiments, the alkoxy group contains 1-20 carbon atoms; in some embodiments, the alkoxy group contains 1-10 9 carbon atoms; in some embodiments, the alkoxy group contains 1-8 carbon atoms; in some embodiments, the alkoxy group contains 1-6 carbon atoms, i.e., C1-6 alkoxy; in some embodiments, the alkoxy group contains 1-4 carbon
11 atoms, i.e., C14 alkoxy.
12 [0051] Examples of alkoxy group include, but are not limited to, methoxy (Me0, -OCH3), ethoxy (EtO, -
13 OCH2CH3), n-propyloxy (n-PrO, n-propoxy, -OCH2CH2CH3), isopropyloxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-
14 butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1 -propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-isopropyloxy (t-BuO, t-butoxy, -0C(CH3)3), etc.
16 [0052] The term "alkylamino" includes "N-alkylamino" and "/V,N-dialkylamino", which means that the 17 amino group is independently substituted with one or two alkyl radicals and the alkyl group is as defined herein.
18 Wherein, the alkylamino group may be optionally substituted with one or more substituents disclosed herein. In 19 some embidiments, the alkylamino group is an alkylamino radical having one or two C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is an alkylamino radical having one or two C14 alkyl 21 groups attached to a nitrogen atom, i.e., C14 alkylamino. Some non-limiting examples of the alkylamino group 22 include methylamino (N-methylamino), ethylamino (N-ethylamino), dimethylamino (/V,N-dimethylamino), 23 diethylamino (N,N-diethylamino), n-propylamino (N-n-propylamino), isopropylamino (N-isopropylamino), etc.
24 [0053] The term "alkylthio" refers to an alkyl group, attached to the parent molecular moiety via a sulfur atom, i.e., -S-alkyl, wherein the alkyl group has the meaning as described in the present invention, wherein the 26 alkylthio group can be optionally substituted by one or more substituents described in the present invention. In some 27 embodiments, the alkylthio group contains 1-10 carbon atoms; in some embodiments, the alkylthio group contains 28 1-8 carbon atoms; in some embodiments, the alkylthio group contains 1-6 carbon atoms, i.e., C1_6 alkylthio; in some 29 embodiments, the alkylthio group contains 1-4 carbon atoms, Le., C14 alkylthio; in some embodiments, the alkylthio group contains 1-3 carbon atoms, i.e., Ci_3 alkylthio. Examples of alkylthio group include, but are not limited to, 31 methylthio, ethylthio, and the like.
32 [0054] The term "haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the 33 haloalkyl group may be optionally substituted with one or more substituents described herein. In some 34 embodiments, the haloalkyl group contains 1-10 carbon atoms; in some embodiments, the haloalkyl group contains 1-8 carbon atoms; in some embodiments, the haloalkyl group contains 1-6 carbon atoms, i.e., CI-6 haloalkyl; in 36 some embodiments, the haloalkyl group contains 1-4 carbon atoms, i.e., CI4 haloalkyl; in some embodiments, the 37 haloalkyl group contains 1-3 carbon atoms, i.e., C1_3 haloalkyl.
Examples of haloalkyl include, but are not limited CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 to, fluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), fluoroethyl (-CHFCH3, -CH2CH2F), 2 di fluoromethyl (-CF2CH3, -CFHCFH2, -CT2CHF2), perfluoroethyl, fluoropropyl (-CHFCH2CH3, -CH2CHFCH3, -3 CH2CH2CH2F), etc.
4 [0055] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen substituents, wherein the haloalkoxy group may optionally be substituted with one or more substituents described herein. In some 6 embodiments, the haloalkoxy group contains 1-10 carbon atoms; in some embodiments, the haloalkoxy group 7 contains 1-8 carbon atoms; in some embodiments, the haloalkoxy group contains 1-6 carbon atoms, i.e., C1_6 8 haloalkoxy; in some embodiments, the haloalkoxy group contains 1-4 carbon atoms, i.e., C1_4 haloalkoxy; in some 9 embodiments, the haloalkoxy group contains 1-3 carbon atoms, i.e., C1_3 haloalkoxy. Examples of haloalkoxy include, but are not limited to, -0CF3, -OCHF2, -OCH2F, and the like.
11 [0056] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups (-12 OH), and the alkyl group has the meaning described in the present invention, wherein the hydroxyalkyl group may 13 be optionally substituted with one or more substituents described herein. In some embodiments, the hydroxyalkyl 14 group described in the present invention refers to a C1-6 alkyl group substituted with one or more hydroxy groups (-OH), i.e., hydroxy C1-6 alkyl; in some embodiments, the hydroxyalkyl group refers to a C14 alkyl group substituted 16 with one or more hydroxy groups (-OH), i.e., hydroxy C14 alkyl. Examples of hydroxyalkyl group include, but are 17 not limited to, hydroxymethyl (e.g., -CH2OH), hydroxyethyl (e.g., 2-hydroxyethyl), and the like.
18 [0057] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups (-NH2), 19 and the alkyl group has the meaning described in the present invention, wherein the aminoalkyl group may be optionally substituted with one or more substituents described herein. In some embodiments, the aminoalkyl group 21 described in the present invention refers to a C1-6 alkyl group substituted with one or more amino groups (-NH2), 22 i.e., amino C1-6 alkyl; in some embodiments, the aminoalkyl group refers to a C14 alkyl group substituted with one 23 or more amino groups (-NH2), i.e., amino C14 alkyl. Examples of aminoalkyl group include, but are not limited to, 24 aminomethyl (-CH2NH2), diaminomethyl (-CH(NH2)2), aminoethyl (e.g., 2-aminoethyl), and the like.
[0058] The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups (-CN), 26 and the alkyl group has the meaning described in the present invention, wherein the cyanoalkyl group may be 27 optionally substituted with one or more substituents described herein.
In some embodiments, the cyanoalkyl group 28 described in the present invention refers to a C1-6 alkyl group substituted with one or more cyano groups (-CN), i.e., 29 cyano C1-6 alkyl; in some embodiments, the cyanoalkyl group refers to a C14 alkyl group substituted with one or more cyano groups (-CN), i.e., cyano C14 alkyl. Examples of cyanoalkyl group include, but are not limited to, 31 cyanomethyl (e.g., -CH2CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
32 [0059] The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxyl groups (-33 COOH), and the alkyl group has the meaning described in the present invention, wherein the carboxyalkyl group 34 may be optionally substituted with one or more substituents described herein. In some embodiments, the carboxyalkyl group described in the present invention refers to a CI-6 alkyl group substituted with one or more 36 carboxyl groups (-COOH), i.e., carboxy C1-6 alkyl; in some embodiments, the carboxyalkyl group refers to a C14 37 alkyl group substituted with one or more carboxyl groups (-COOH), i.e., carboxy C14 alkyl. Examples of CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 carboxyalkyl group include, but are not limited to, carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and the like.

[0060] The term "cycloalkyl" or "carbocycly1" refers to a monocyclic, bicyclic or tricyclic ring systems having from 3 to 14 ring carbon atoms, saturated or partially unsaturated, having one or more points of attachment 4 to the rest of the molecule. Wherein the cycloalkyl group is optionally substituted with substituents described herein.
In some embodiments, the cycloalkyl is a ring system containing 3-10 ring carbon atoms, i.e., C3-10 cycloalkyl; in still other embodiments, the cycloalkyl is a ring system containing 3-8 ring carbon atoms, i.e., C3_8 cycloalkyl; in yet other embodiments, the cycloalkyl is a ring system containing 3-6 ring carbon atoms, i.e., C3-6 cycloalkyl.

Examples of cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 9 cyclopentadienyl and the like.
[0061] The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms of which at least one ring member is selected from nitrogen, sulfur, oxygen and phosphorus. Wherein, the heterocyclyl is non-aromatic and does not contain any aromatic ring, and the ring system has one or more connection points connected to the rest of the molecule. Wherein, the heterocyclyl may be optionally substituted with one or more substituents disclosed herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, Spiro or bridged heterocyclic ring systems.

Bicyclic heterocyclyl includes bridged bicyclic heterocyclyl, fused bicyclic heterocyclyl and spirobicyclic heterocyclyl. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. Unless otherwise specified, the heterocyclyl group may be carbon or nitrogen linked, and a -CH2-group can be optionally substituted with -C(=0)-. In which, the sulfur can be optionally oxygenized to S-oxide, the nitrogen can be optionally oxygenized to N-oxide, and the phosphorus can be optionally oxygenized to P-oxide. In some embodiments, the heterocyclyl is a ring system consisting of 3-10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-10 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 5-8 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 6-8 atoms; in some embodiments, the heterocyclyl is 24 a ring system consisting of 5-6 atoms, i.e., a heterocyclyl consisting of 5-6 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 3-6 atoms, i.e., a heterocyclyl consisting of 3-6 atoms; in some embodiments, the heterocyclyl is a ring system consisting of 3 ring atoms; in some embodiments, the heterocyclyl 27 is a ring system consisting of 4 atoms; in other embodiments, the heterocyclyl is a ring system consisting of 5 atoms;
28 in other embodiments, the heterocyclyl is a ring system consisting of 6 atoms.

[0062] Some non-limiting examples of the heterocyclyl group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 31 tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, 32 tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, tetrahydropyrrolyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydropyrazinyl, tetrahydropyridazinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, and the like. Some non-limiting examples of heterocyclyl wherein -CH2- group is replaced by -C(=0)- include 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, pyrimidinedione-yl, 3,4-dihydroisoquinolin-1(211)-one. Some non-limited examples of heterocyclyl wherein the CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 ring sulfur atom is oxidized is sulfolanyl and 1,1-dioxo-thiomorpholinyl.
Bridged heterocyclyl groups include, but 2 are not limited to, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and the like.
3 [0063] The term "consisting of m atoms" where m is an integer typically describes the number of ring-4 forming atoms in a moiety where the number of ring-forming atoms is m.
For example, piperidinyl is a heterocyclyl group consisting of 6 atoms and furyl is a heteroaryl group consisting of 5 atoms. As another example, "heterocyclyl 6 consisting of 3-6 atoms" refers to a heterocyclyl group consisting of 3, 4, 5 or 6 atoms.
7 [0064] The term "aryl" refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems 8 containing 6-14 ring atoms, or 6-10 ring atoms, wherein each ring contains 3-7 ring atoms and has a single point or 9 multipoint of attachment to the rest of the molecule. Wherein the aryl may be optionally substituted with one or more substituents disclosed herein. The term "aryl" may be used interchangeably with the term "aromatic ring".
11 Examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, and anthracenyl, etc.
12 [0065] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic aromatic systems containing 5-14 13 ring atoms, wherein at least one ring contains one or more heteroatoms, the entire ring system is aromatic, and the 14 heteroaryl has a single point or multipoint of attachment to the rest of the molecule. Wherein the heteroaryl may be optionally substituted with one or more substituents disclosed herein. Unless otherwise stated, the heteroaryl group 16 can be attached to the rest of the molecule (such as the main structure in the general formula) through any reasonable 17 point (which can be C in CH, or N in NH). When a -C112- group is present on a heteroaryl group, the -CH2- group 18 may optionally be replaced by a -C(=0)-. The term "hetreroaryl" and "heteroaromatic ring" or "heteroaromatic 19 compound" can be used interchangeably herein. In some embodiments, heteroaryl is a heteroaryl consisting of 5-8 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from 0, S, and N; in some embodiments, 21 heteroaryl is a heteroaryl consisting of 5-7 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from 22 0, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 5-6 atoms comprising 1, 2, 3 or 4 23 heteroatoms independently selected from 0, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting 24 of 5 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from 0, S, and N; in some embodiments, heteroaryl is a heteroaryl consisting of 6 atoms comprising 1, 2, 3 or 4 heteroatoms independently selected from 0, 26 S, and N
27 [0066] Examples of heteroaryl groups include, but are not limited to, the following monocyclic groups: furyl 28 (2-furyl, 3-furyl), imidazolyl (N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazoly1), isoxazolyl (3-isoxazolyl, 4-29 isoxazolyl, 5-isoxazolyl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazoly1), pyrrolyl (N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridy1), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), 31 pyridazinyl (such as 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazoly1), thienyl (2-thienyl, 3-thienyl), 32 pyrazolyl (such as 2-pyrazoly1 and 3-pyrazoly1), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-33 oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl;
34 and also include, but are by no means limited to, the following bicyclic or tricyclic groups: benzimidazolyl, benzofuryl, benzothienyl, indolyl (such as 2-indoly1), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinoly1), 36 isoquinolyl (such as 1-isoquinolyl, 3-isoquinoly1 or 4-isoquinoly1), dibenzoimidazolyl, dibenzofuryl, 37 dibenzothienyl.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 [0067] The term "cycloalkyl-alkylene" refers to a cycloalkyl group attached to the rest of the molecule through an alkylene group, wherein the cycloalkyl and alkylene are as defined herein. The "cycloalkyl-alkylene"

group may be optionally substituted with one or more substituents disclosed herein. The "C3_6 cycloalkyl-C14 alkylene" mentioned in the present invention means that the C3-6 cycloalkyl is linked to the rest of the molecule through a C14 alkylene group. The "C3_6 cycloalkyl-C1_2 alkylene" mentioned in the present invention means that the C34 cycloalkyl is linked to the rest of the molecule through a C1_2 alkylene group. Such examples include, but are not limited to, cyclopropyl-CH2-, cyclopropyl-CH2CH2-, cyclobutyl-CH2-, cyclobutyl-CH2CH2-, cyclopentyl-8 CH2-, cyclopentyl-CH2CH2 cyclohexyl-CH2-, cyclohexyl-CH2CH2-, etc.

[0068] The term "heterocyclyl-alkylene" refers to a heterocyclyl group attached to the rest of the molecule through an alkylene group, wherein the heterocyclyl and alkylene are as defined herein. The "heterocyclyl-alkylene"

group may be optionally substituted with one or more substituents disclosed herein. The "(heterocyclyl consisting 12 of 5-6 atoms)-C14 alkylene" mentioned in the present invention means that the heterocyclyl consisting of 5-6 atoms 13 is linked to the rest of the molecule through a C14 alkylene group. The "(heterocyclyl consisting of 5-6 atoms)-CI-2 alkylene" mentioned in the present invention means that the heterocyclyl consisting of 5-6 atoms is linked to the rest of the molecule through a C1-2 alkylene group. Such examples include, but are not limited to, tetrahydropyranyl-16 CH2-, tetrahydropyranyl-CH2CH2-, tetrahydrofuranyl-CH2-, tetrahydrofuranyl-CH2CH2-, pyrrolidinyl-CH2-, 17 piperidinyl -CH2-, piperidinyl-CH2CH2-, morpholinyl-CH2-, morpholinyl-CH2CH2-, and the like.

[0069] The term "aryl-alkylene" refers to an aryl group attached to the rest of the molecule through an alkylene group, wherein the aryl and alkylene are as defined herein. The "aryl-alkylene" group may be optionally substituted with one or more substituents disclosed herein. For example, the "C6_10 aryl-C14 alkylene" mentioned in the present invention means that the C6-10 aryl is linked to the rest of the molecule through a C14 alkylene group.

The "C6_10 aryl-C1_2 alkylene" mentioned in the present invention means that the C6-10 aryl is linked to the rest of the molecule through a C1_2 alkylene group. Such examples include, but are not limited to, phenyl-CH2-, phenyl-24 CH2CH2-, naphthyl-CH2-, and the like.
[0070] The term "heteroaryl-alkylene" refers to a heteroaryl group attached to the rest of the molecule through an alkylene group, wherein the heteroaryl and alkylene are as defined herein. The heteroaryl-alkylene group may be optionally substituted with one or more substituents disclosed herein.
The "(heteroaryl consisting of 5-6 atoms)-C14 alkylene" mentioned in the present invention means that the heteroaryl consisting of 5-6 atoms is linked 29 to the rest of the molecule through a C14 alkylene group. The "(heteroaryl consisting of 5-6 atoms)-C1-2 alkylene"
mentioned in the present invention means that the heteroaryl consisting of 5-6 atoms is linked to the rest of the molecule through a C1_2 alkylene group. Such examples include, but are not limited to, pyridyl-CH2-, pyrrolyl-32 CH2CH2-, quinolinyl-CH2-, thienyl-CH2-, furyl-CH2-, pyrimidyl-CH2-, pyridyl-CH2-, etc.

[0071] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus and silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as in 3,4-dihydro-2H-pyrroly1), NH (as in pyrrolidinyl) 36 or NV (as NRT in N-substituted pyrrolidinyl, RT is a substituent on N).

[0072] The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl" or "acyloxy", CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 represents -(C=0)-.
2 [0073] The term "deuterium" means deuterated, i.e., 2H.
3 [0074] The term "pharmaceutically acceptable" means that the substance or composition must be chemically 4 and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a 6 regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally 7 recognized pharmacopeia for use in animals, and more particularly in humans.
8 [0075] The term "carrier" includes any solvent, dispersion medium, coating material, surfactant, 9 antioxidant, preservative (such as antibacterial, antifungal), isotonic agent, salt, drug stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, these carriers are known to those 11 skilled in the art (such described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, 12 pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in 13 therapeutic or pharmaceutical compositions is contemplated.
14 [0076] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, and other chemical 16 components, such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and 17 other auxiliary materials, and other additional therapeutic agents, such as anti-diabetic agents, antihyperglycemic 18 agents, antiadipositas agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering 19 agents, etc. The purpose of the pharmaceutical composition is to facilitate administration of a compound to an organism.
21 [0077] The term "prodrug" refers to a compound that is transformed in vivo into a compound of Formula 22 (I). Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic 23 transformation to the parent form in blood or tissue. Prodrugs of the compounds disclosed herein may be, for 24 example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1_24.) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein 26 that contains a hydroxy group may be acylated at this position in its prodrug form. Other prodrug forms include 27 phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent 28 compound. A thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, 29 Vol. 14, A.C.S. Symposium Series; Roche, et al. ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs:
Design and Clinical Applications, 31 Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J.
32 Med. Chem., 2008, 51, 2328-2345.
33 [0078] The term "metabolite" refers to a product produced through metabolism in the body of a specified 34 compound or salt thereof The metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example 36 from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, 37 and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a 2 sufficient time period.
3 [0079] The term "pharmaceutically acceptable salt" refers to organic or inorganic salts of a compound 4 disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, the pharmaceutically acceptable salts are described in detail in Berge et al., J. Pharmacol Sci, 1977, 66: 1-19, which is incorporated herein 6 by reference in its entirety.
7 [0080] The term "solvate" refers to an association or complex of one or more solvent molecules and a 8 compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, 9 isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.
11 [0081] The term "N-oxide" refers to one or more than one nitrogen atoms oxidised to form an N-oxide, 12 where a compound contains several amine functions. Particular examples of N-oxides are the N-oxides of tertiary 13 amines or the N-oxides of nitrogen atoms of nitrogen-containing heterocycle. N-oxides can be formed by treatment 14 of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages).
16 More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which 17 the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such 18 as dichloromethane.
19 [0082] Any asymmetric atom (e.g., carbon or the like) of the compound(s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R, S)-configuration. In certain embodiments, 21 each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 %
22 enantiomeric excess, at least 80 % enantiomeric excess, at least 90 %
enantiomeric excess, at least 95 %
23 enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Where possible, 24 substituents on atoms with unsaturated double bonds may be present in cis-(Z)- or trans-(E)-form.
[0083] Therefore, as described herein, the compounds of the present invention may exist in the form of one 26 or a mixture of possible isomers, rotamers, atropisomers, tautomers, for example in the form of substantially pure 27 geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
28 [0084] Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical 29 differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization. Cis and trans isomers are diastereomer.
31 [0085] Any resulting racemates of fmal products or intermediates can be resolved into the optical antipodes 32 by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof. Racemic products 33 can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral 34 adsorbent. Preferred enantiomers can also be prepared by asymmetric syntheses. (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed.
36 Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E.L.
Stereochemistry of Carbon Compounds 37 (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972))) [0086] The invention also includes isotopically labeled compounds of the invention which are identical to those described herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from that found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, 6 such as 2H, 3H, 13C, 14C, 15N, 160, 170, 31p, 32p, 36s, 18F and 37C1, respectively.

[0087] Compounds of the present invention comprising the aforementioned isotopes and/or other isotopes 8 of other atoms, as well as pharmaceutically acceptable salts of the compounds, are included within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred due to ease of preparation and detection. Furthermore, substitution with a higher mass isotope, such as deuterium, i.e., 211, may afford some therapeutic advantage of greater metabolic stability, such as increasing in vivo half-life or reducing dosage 14 requirements. Therefore, it may be preferable in some situations.
[0088] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York;
and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatoiy. For a given chemical structure, these stereoisomers are identical except that they are mirror images 27 of each other. A specific stereoisomer is referred to as an enantiomer, and a mixture of such isomers is often called 28 an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which 29 may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
[0089] Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as pure optical isomers, or as mixtures of isomers, e.g., as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms.

Optically active (R)- and (5)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration.

[0090] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomer, and geometric (or conformational)) forms of the structure; for example, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers for each 2 asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric 3 mixtures of the present compounds are within the scope disclosed herein.
4 [0091] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g., in solution), a chemical 6 equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) 7 include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence 8 tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-9 enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. The specific example of phenol-keto tautomerisms is 11 pyridin-4-ol and pyridin-4(1H)-one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds 12 disclosed herein are within the scope of the invention.
13 [0092] The term "geometric isomer" is also called "cis-trans isomer", which are isomers caused by double 14 bonds (including the double bond of olefin, C=N double bond and N=N
double bond) or single bonds of ring carbon atoms that cannot rotate freely.
16 [0093] As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject 17 also refers to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the 18 like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
19 [0094] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), particularly "mammals"
21 including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs and mice) and primates 22 (e.g., monkeys, chimpanzees and humans), more particularly humans. In one embodiment, the subject is a non-23 human animal, such as a livestock (e.g., horse, cow, pig, or sheep) or pet (e.g., dog, cat, guinea pig, or rabbit). In 24 other embodiments, "patient" refers to a human.
[0095] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds 26 that differ only in the presence of one or more isotopically enriched atoms.
27 [0096] As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one 28 embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the 29 disease or at least one of the clinical symptoms thereof). In another embodiment, "treat", "treating" or "treatment"
refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible 31 by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or 32 disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a 33 physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or 34 delaying the onset or development or progression of the disease or disorder.
DESCRIPTION OF COMPOUNDS OF THE INVENTION
36 [0097] The invention provides a class of compounds with good agonistic activity on thyroid hormone 13 37 receptors, which are used in the manufacture of a medicament for treating neurodegenerative diseases, nonalcoholic CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 fatty liver diseases, liver Fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, 2 hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, 3 metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
4 The present invention also provides methods for preparing these compounds, pharmaceutical compositions containing these compounds, and methods for using these compounds and pharmaceutical compositions in the 6 manufacture of a medicament for treating mammals, especially human beings, for the above-mentioned diseases.
7 Compared with the existing similar compounds, the compounds of the present invention not only have good 8 pharmacological activity and selectivity, but also have excellent in vivo metabolic kinetic properties and in vivo 9 pharmacodynamic properties. The preparation methods of the compounds described in the invention are simple and easy, the process methods are stable, and are suitable for industrialized production. Therefore, the compounds 11 provided by the present invention have better druggability than the existing similar compounds.
12 [0098] Specifically:
13 [0099] In one aspect, the present invention provides a compound having Formula (I) or a stereoisomer, a 14 geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, R3d Rc A
___________________________________________________ R3a N N "R2 R3b N

17 wherein, ring A, Y, R', R2, R3a, R31', R3c and R3d have the definitions as described in the present invention.
18 [00100] In some embodiments, Y is -0-, -S-, -NR -, -C(=0)-, C1_6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 19 -NR C(=0)- or -C(=0)NR -; wherein the Y is optionally substituted with 1, 2 or 3 Rx; wherein the R and Rx have the definitions as described in the present invention.
21 [00101] In some embodiments, R is H, deuterium, C1-6 alkyl, C1-6 haloalkyl, hydroxy C1-6 alkyl, amino CI-6 22 alkyl or cyano CI-6 alkyl.
23 [00102] In some embodiments, R is H, deuterium, methyl, ethyl, n-propyl, isopropyl, C1_4. haloalkyl, 24 hydroxymethyl, hydroxyethyl, aminomethyl or cyanomethyl.
[00103] In some embodiments, each of R3a, R31', R3C and R3d is independently H, deuterium, F, Cl, Br, I, -CN, 26 -NO2, -COOH, -OH, -NH2, -SH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 haloalkyl, C1-6 27 haloalkoxy, hydroxy CI-6 alkyl, amino CI-6 alkyl or cyano CI-6 alkyl.
28 [00104] In some embodiments, R' is H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C1-6 29 alkyl, C2_6 alkenyl, C2_6 alkynyl, -C(=0)-C1_6 alkoxy, -C(=0)-C1_6 alkyl, -C(=0)-C1_6 alkylamino, -C(=0)NH2, -S
(=0)2-C1-6 alkyl, -S(=0)2-C1-6 alkylamino, -S(=0)2NH2, C1-6 alkylamino, C1-6 alkoxy, CI-6 haloalkyl, C1-6 31 haloalkoxy, hydroxy CI-6 alkyl, amino CI-6 alkyl, carboxy CI-6 alkyl or cyano CI-6 alkyl.
32 1001051 In some embodiments, R2 is H, deuterium, C1,6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_6 cycloalkyl, 33 heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00106] In some embodiments, R2 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, C24 alkenyl, 2 C24 alkynyl, C3_6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, phenyl or heteroaryl consisting of 5-6 atoms.
E Ui E4 (LJ u3sgCS' E6 3 [00107] In some embodiments, ring A is 0 , 0 0 or zi z3 4 R5 ;
wherein, ring A may be optionally substituted by 1, 2 or 3 RY; the El, E2, E3, Ea, ES, E6, Ul, U2, U35 Z1, Z2, Z3, R5 and RY have the definitions described in the present invention.
6 [00108] In some embodiments, each of El, Ul and Zi is independently -(CR4aR4b)q-, -C(=0)-, -0-, -S-, -7 S(=0)-, -S(=0)2- or -NRa-; the R4a, R41', Ra and q have the definitions described in the present invention.
8 [00109] In some embodiments, each of E2, U2 and Z2 is independently -CR4eR4d-, -C(=0)-, -0-, -S-, -S(=0)-9 , -S(=0)2- or -NR"-; the R4e, R4d and Rb have the definitions described in the present invention.
[00110] In some embodiments, each of E3, E6, U3 and Z3 is independently -CR4eR41' -, -C(=0)-, -0-, -S-, -11 S(=0)-, -S(=0)2- or -NRe-; the R4e, R4f and Re have the definitions described in the present invention.
12 [00111] In some embodiments, E4 is -CR4g= or -N=; wherein, the R4g has the definition described herein.
13 [00112] In some embodiments, Es is -CR4h= or -N=; wherein, the R4I1 has the definition described herein.
14 [00113] In some embodiments, q is 0, 1, 2 or 3.
[00114] In some embodiments, each Ra, R", Ra and R5 is independently II, deuterium, C14 alkyl, C2-6 alkenyl, 16 C2-6 alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting 17 of 5-6 atoms, wherein each Ra, Rb, Re and R5 is independently and optionally substituted with 1, 2 or 3 RYI, RYI has 18 the meaning described in the present invention.
19 [00115] In some embodiments, each R4a, Rab, Rae, R4d, R4e, R41', Rag and R4b is independently H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C1_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C1-6 alkoxy, C1-6 alkylamino, 21 C1_6 haloalkyl, C1_6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkyl-C14 alkylene, heterocyclyl consisting of 5-6 atoms, 22 (heterocyclyl consisting of 5-6 atoms)-C14 alkylene, C6-10 aryl, C6-10 aryl-C14 alkylene, heteroaryl consisting of 5-23 6 atoms or (heteroaryl consisting of 5-6 atoms)-C14 alkylene, wherein each R4a, Rat), Rae, Rad, Rae, R41' , R4 and R4I1 24 is optionally substituted with 1, 2 or 3 RY2, RY2 has the definition as described in the present invention.
[00116] In some embodiments, R4a and R41', together with the carbon atoms to which they are attached, form 26 a C3_8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3_8 carbon ring and heterocyclyl 27 consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 RY3, RY3 has the definition described 28 in the present invention.
29 [00117] In some embodiments, R4e and R4d, together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-8 carbon ring and heterocyclyl 31 consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 RY1, RY' has the definition described 32 in the present invention.
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 [00118] In some embodiments, R4e and Wif, together with the carbon atoms to which they are attached, form 2 a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-8 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 RY3, RY3 has the definition described 4 in the present invention.
[00119] In some embodiments, two RY linked on adjacent atoms, together with the atoms to which they are attached, form a C3_8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3_8 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY4, RY4 has the 8 definition described in the present invention.

[00120] In some embodiments, each W is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C1-6 alkyl, C1-6 haloalkyl, Ci_6 haloalkoxy, C1-6 alkoxy or C1-6 alkylamino.

[00121] In some embodiments, each Rx is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, 13 methoxy, ethoxy, isopropoxy, methylamino or dimethylamino.

[00122] In some embodiments, each RY is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, C1-6 alkyl, C1_6 haloalkyl, C1_6 haloalkoxy, C1-6 alkoxy or C1-6 alkylamino.

[00123] In some embodiments, each RY is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, 18 methoxy, ethoxy, isopropoxy, methylamino or dimethylamino.

[00124] In some embodiments, each RYI is independently deuterium, F, Cl, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-C1-6 alkyl, -C(=0)-C1-6 alkoxy, -C(=0)-C1-6 alkyl, -C(=0)-C1-6 alkylamino, -C(=0)NH2, -S(=0)2-C1-6 alkyl, -S(=0)2-C1_6 alkylamino, -S(=0)2NH2, Ci_6 alkyl, CI-6 haloalkyl, C1_6 haloalkoxy, C1_6 alkoxy, CI-6 alkylthio, Ci_6 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each RY1 is independently and optionally substituted with 1, 2 or 3 W, W has the definition described 24 in the present invention.
[00125] In some embodiments, each Rz, RY2, RY3 and RY4 is independently deuterium, F, Cl, Br, I, -CN, -OH, 26 -NH2, -COOH, C1_6 alkyl, C1_6 haloalkyl, C1_6 haloalkoxy, C1_6 alkoxy, C1_6 alkylthio or C1_6 alkylamino.

[00126] In some embodiments, each of R3d, R31', R3c and R3d is independently H, deuterium, F, Cl, Br, I, -CN, NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl or cyanomethyl.
[00127] In some embodiments, RI is H, deuterium, F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, 31 ethyl, n-propyl, isopropyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -C(=0)-OCH3, -C(=0)-OCH2CH3, -C(=0)-OCH(CH3)2, -C(=0)-OCH2CH2CH3, -C(=0)-0(CH2)3CH3, -C(=0)-OCH2CH(CH3)2, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-NHCH3, -C(=0)-N(CH3)2, -C(=0)NH2, -S(=0)2-CH3, -S(=0)2-CH2CH3, -S(=0)2-NHCH3, -S(=0)2NH2, methylamino, ethylamino, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.

[00128] In some embodiments, each Ra, Rb, W and R5 is independently H, deuterium, Ci alkyl, C2-4 alkenyl, C24. alkynyl, Ci haloalkyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 of 5-6 atoms, wherein each Ra, R", RC and R5 is independently and optionally substituted with 1, 2 or 3 RY', RY' has 2 the meaning described in the present invention.

[00129] In some embodiments, each Ra, Rb, Rc and R5 is independently H, deuterium, methyl, ethyl, n-propyl, 4 isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, 6 tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, 7 thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein each Ra, Rb, RC and R5 8 is independently and optionally substituted with 1,2 or 3 WI, RY1 has the meaning described in the present invention.

[00130] In some embodiments, each RY1 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-C14 alkyl, -C(=0)-C14 alkoxy, -C(=0)-C14 alkyl, -C(=0)-C14 alkylamino, -C(=0)NH2, -S(=0)2-C14 11 alkyl, -S(=0)2-C14 alkylamino, -S(=0)2NH2, C14 alkyl, C14 haloalkyl, C14 haloalkoxy, C14 alkoxy, C14 alkylthio, 12 C14 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 13 atoms, wherein each V is optionally substituted with 1, 2 or 3 122, R2 has the definition described in the present 14 invention.
[00131] In some embodiments, each RY1 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -SH, oxo, 16 -0C(=0)-methyl, -0C(=0)-ethyl, -0C(=0)-n-propyl, -0C(=0)-isopropyl, -0C(=0)-n-butyl, -0C(=0)-tert-butyl, -17 OC(=0)-isobutyl, -C(=0)0-methyl, -C(=0)0-ethyl, -C(= 0)0-n-propyl, -C(=0)0-isopropyl, -C(=0)0-n-butyl, -18 C(=0)0-tert-butyl, -C(=0)0-isobutyl, -C(=0)-methyl, -C(=0)-ethyl, -C(=0)-n-propyl, -C(=0)-isopropyl, -C
19 (=0)-n-butyl, -C(=0)-tert-butyl, -C(=0)-isobutyl, -C(=0)-methylamino, -C(=0)-ethylamino, -C(=0)NH2, -S(=0)2-C1-3 alkyl, -S(=0)2-C1-3 alkylamino, -S(=0)2NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -21 CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, 22 ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl, 23 cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, 24 piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, fury!, thienyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each RY1 is optionally substituted with 1, 2 or 3 R2;
26 wherein R2 has the meaning described in the present invention.

[00132] In some embodiments, each R", Rzib, Rac, Rad, Rae, Rat, R4g and R" is independently H, deuterium, 28 F, Cl, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH-CH2, 29 -CH2CH=CH2, -CH=CHCH3, methoxy, ethoxy, methylamino, ethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, 31 cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, 32 tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, 33 tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, thiomoipholinyl-CH2-, 34 piperazinyl-CH2-, phenyl, phenyl-CH2-, phenyl-CH2CH2-, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-36 , pyridyl-CH2- or pyrrolyl-CH2-, wherein each R4a, R4b, Tic, Rad, Rae, Rat, Rag and rc T.4h is independently and optionally 37 substituted with 1, 2 or 3 RY2, RY2 has the definition described in the present invention.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 [00133] In some embodiments, Itta and R41', together with the carbon atoms to which they are attached, form 2 a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-6 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 V, RY3 has the definition described 4 in the present invention.
[00134] In some embodiments, R4e and R4d, together with the carbon atoms to which they are attached, form 6 a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3_6 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 V, V has the definition described 8 in the present invention.

[00135] In some embodiments, R4e and R41', together with the carbon atoms to which they are attached, form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-6 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted by 1, 2 or 3 V, V has the definition described 12 in the present invention.

[00136] In some embodiments, each Rz, V, V and IV' is independently deuterium, F, Cl, Br, I, -CN, -OH, NH2, -COOH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -OCH2F, methoxy, ethoxy or methylamino.

[00137] In another aspect, the present invention provides one of the following structures, or a stereoisomer, 17 a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug 18 thereof, ci ci , HN y CI -\ ), N i-NH N
N NH
CI

-r 0 19 CN (1), CN (2), ci ci 0 0,,, N CI N NH J, 0 I I I , ji , (:) ¨ ,- ,,--11 (:)''N-1-r¨
ci- - '.--Isl NH
0 0 r,-) CN (3), CN (4), CI Cl Ci H\N---_,/(- ,-¨ - CI N NH CI N NH

CI' N NH H
,, 1 0 0 r`ly-0 '6 21 CN (5), C00Me (6), CN
(7), ?i 0 Cl H U , 0 I
ON1:: 0 HN' y y i 0 õ-11-. 1 C1 N. .NH "-i CI --' N 'U NH
N
'r0 0 22 ON (8), CN (9), CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI
CI

'0-------ni "-- Cl- - N NH CI N NH
0 ri' 0 0 1 ON (10), coome (11), CI a - - o c?'-'i r 1 1 ,N I _2.1- Xõ..--/
CI N NH I,O,N, CI NNH
0 N , 0 Nytõ0 -r 0 2 ON (12), CN (13), Cl Cl F -- '----- Cl'' 'N NH F,-FON
CI N 11,NH
0 Ny-o 0 No 3 CN (14), ON (15), CI
n I Cl .-, ...,,,, 0 0 NH HN, =- ,H, It 1, 0 I4. -t r - Cr- ' N NH
y -0 4 ON (16), ri ¨ 0 (17), CI

r 0 HN
N)-LNH
N -¨ li CI- N NH CI
0 r 0 IV
T o o CN (18), CN (19), Cl CI
F.

''F. NH F, r Cl Ni NH

ri l''LO
0 N..,,L
6 CN (20d), -0 (20), CI
0 a o CI
O.
NNH
0 lyL 411 NI
a o o r"o 7 CN (21d), (21), CI a o o o o N

N)tNH
N
a, , NNH

I CI
0 IV 0 lo 8 o (22), (23), Cl I Cl N ro ,,...
0 , 0 1 ICL r 0,1, 0 N
11 ci¨,c----Nj.LNH
-, ' N 1 10 CIN-jtNH
0 IV,o 9 CN (24d), (24), CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI
r ---0 CI
n 1 ' '1,a, Ji 0 N,N ,N - --"" - 0 CI N NH n 0 N NNIN1,,, I
CI ) 1 CN (25d), o (25), 0 i CI

1 ' H
N NH

HN ,..T * N CI
,..., ' N NH
0 N , 0 N y, 2 CN (26), CN
(27), Cl o a I CI N NH
* N 0 A

NH
3 CN (28g), F
(28), CI
CI F:Ca -, -0 F3C 0 0 la 0 ff, I / N.JNH
N F N. CI 1 CI 1111-1 NINH O N , 4 o (29), CN
(30d), CI
CI i" ¨, .o.
F Al NI 1 9 0 F,,,- )sl CI N NH
F 41111111 ti CI 14-11'NH 0 NI -yo o (30), CN (31d), F CI
C( 0 F W 1 CI:- a -1%1NH
-,' 0 N 'r -0 6 0 (31), CN
(32d), CI
F 0 CI - (21,.- 0 0 n r---1- -,-. 1 0 NANH,---,-, .1.
1---- N CI'' N NH
F . N CI
0 N F 0 N ,:) 7 o (32), (33d), CI CI
0 N 0 1 & &V-V Od CI t'-3 N NH F3C- - CI' N NH

8 o (33), o (34), CI
F, , ---, -0,--L a --, 0 CV y CI It N NH 0 ci 0 NNH

rLõ,k,o 9 CN (35d), (35), CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI CI
CI
Me0 100 N

N ,C, N)-NH CI

(36), 0 (37), 1 o Cl CI 0 ,J, 0 HO õN. ,'-N
N NH CI
CI y I
0 NIcc TIINI NH
)- 0 '0 2 CN (38), CN
(39), F,L l' J

-'N'C'-- CI' -- -- 'N NH

,.,,,,L.
3 CN (40d), -o (40), CI

F3c0 0 o idk 0 N ANH

CI
NQ N'ell'NH
0 No 0 rj 0 (42), (41), Cl Cl F
J---._,- ,r, 0------ ----.,..,õ -- 0 11 1 ' 1 Jt 401 N CI -1 N A NH 1 , ,,---- Cl --N 'NH
a 11 0 N 0 (43), N , -o (44), CI
CI

I
n 0 L
N -1,N --CI N 1 NH 'N N 01 q& I
W 'N - 'NH
0 NI (45), 0 N,,,0 (46), o Cl 0 Cl N i , ) ) N Cl2' 1-, 0 , N ,ro NiNH
1:1 0 o (47), 7 CN (470, ClCl --,, 0 ri ) 1 il "j-NH
N
NJ' r'i' CI 1 - ' 0IN' 'NH 11 ) 0 --r" -0 8 (48), N. 0 N , ,I
ON
(490, C
Cl I
o 0 ¨ -0 -----1,-õ, 0 I I
rm - 1 Jt rsirtµl l_r ci-- N NH
-N ..- :
N ,L
N - CI' N NH N 0 -- y -o k ,J 0 ri ,L
CN
(500, 9 -- -0 (49), CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI
I

CI
J,,NNH 1 1 1 NH
,NNI.,r2 (50), CN
(51), CI

N-y N
I

C ,N
..-- S 0 1 N0 (52), o ci 0 N).NH
N0 (53), 2 ci nal Br CI
I

CI N NH
Br N NH N , 0 j 6 ii I

3 CN (54), ON
(55), F CI CI

,}21,, I , 0 I ' HN II IT Cr 1NNH HN,, CI_,-, -, N
NH

N y'c) 0 4 CN (56), CN (57), CI

, 0 o I 1 0 N)-NH
'NINH --,s, --õN
If CI
0 N.-õ,---,-. 0 N
CN (58), CN (59), CI a CI
r r.J L ? HN ra 1 0 N1 =
CI N' 'NH CI 'µ' N NH HN CI N
NH
0 IV , ,L 0 fyLo 0 ri.,IAo y -o 6 CN (60), CN (61), CN (62), CI CI
0.y ..-1-,.õ 0 -HN
NANH FO rilyTL/ CI)-i.,.NANH
CI I
0 rjy-LO F 0 14 J-y -0 7 CN (63), CN (64), CI CI

F, N Ai C
F 0 0 \ \ * I
CI 11' KI'LL'NH S'-'N CI N NH
o ri-,Ao ri 8 (65), o -'4o (66), Cl CI

NANH A,,,N
CINJ-NH
0 ni,_L 0 11,,Lo 9 `o (67), (68), CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI

Br 0 F 0 _ 0 NI I ; I
N
N A N H CI N
NH
CI
0 N ,,, 1 -o (69), (70), ci CI

HN
N
HN J-LN CI' CI

,,,L.
2 NH 0 (71), H0 (72), CI F CI
F. 0 N I N NH F0 0 N
.. NJLNH

0 N .k. 0 3 o (73), N 0 (74), ci \ c .0 l Y' ii 0 0 HN, 4 .N1J-NH

idli N if ci CI 0 N"-ItNH 0 f`1.-1,-.- ------4 F3c- 41111-1" 0(75) or CN (76).
[00138] In other aspect, provided herein is a pharmaceutical composition comprising the compound disclosed 6 herein.

[00139] In some embodiments, the pharmaceutical composition disclosed herein optionally further comprises 8 any one of a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle or any combination thereof.

[00140] In another aspect, the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in the manufacture of a medicament for stimulating thyroid 11 hormone receptors; or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[00141] In another aspect, the present invention relates to a method of stimulating thyroid hormone receptors with the compound or the pharmaceutical composition of the present invention, or a method of preventing, treating 14 or alleviating diseases regulated by thyroid hormone receptors in a subject comprising administering to the subject a therapeutically effective amount of the compound or the pharmaceutical composition of the present invention.

Moreover, the above-mentioned compounds provided by the present invention or their pharmaceutical compositions can be co-administered with other therapies or therapeutic agents. The mode of administration can be carried out 18 simultaneously, sequentially or at certain time intervals.

[00142] In another aspect, the present invention relates to the compound of the present invention or the pharmaceutical composition of the present invention for use in stimulating thyroid hormone receptors, or in 21 preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[00143] In some embodiments, the thyroid hormone receptor of the present invention is a thyroid hormone 13 23 receptor.

[00144] In some embodiments, the diseases regulated by thyroid hormone receptors in the present invention are neurodegenerative diseases, nonalcoholic fatty liver diseases, idiopathic pulmonary fibrosis, atherosclerosis, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, 2 obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, 3 hypothyroidism or thyroid cancer.
4 [00145] In one aspect, the present invention relates to use of the compound of the present invention or the pharmaceutical composition of the present invention in the manufacture of a medicament for preventing, treating or 6 alleviating the following diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, 7 idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, 8 hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism 9 disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
[00146] In one aspect, the present invention relates to the compound of the present invention or the 11 pharmaceutical composition of the present invention for use in preventing, treating or alleviating the following 12 diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, idiopathic pulmonary fibrosis, 13 atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, 14 dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
16 [00147] In one aspect, the present invention relates to a method of using the compound of the present 17 invention or the pharmaceutical composition of the present invention to prevent, treat or alleviate the following 18 diseases: neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, idiopathic pulmonary fibrosis, 19 atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease 21 type 1A, hypothyroidism or thyroid cancer. The method is administering to an individual in need thereof a 22 therapeutically effective amount of the compound or the pharmaceutical composition.
23 [00148] In some embodiments, the nonalcoholic fatty liver disease described in the present invention is 24 nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis associated with nonalcoholic fatty liver disease or primary liver cancer.
26 [00149] In some embodiments, the neurodegenerative disease described in the present invention is 27 demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, 28 multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy (ALD), amyotrophic lateral sclerosis (ALS) or 29 Alzheimer's disease.
[00150] The dosage of the compound or pharmaceutical composition required to implement the effects of 31 treatment, prevention or delay usually depends on the specific compound to be administered, the patient, the specific 32 disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by 33 the attending physician according to the actual situation. For example, when the compounds or pharmaceutical 34 compositions provided by the present invention are administered by intravenous route, the administration can be performed once a week or even at longer time intervals.
36 [00151] In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term 37 "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
2 [00152] The compounds of the present invention also include other salts of such compounds, which are not 3 necessarily pharmaceutically acceptable salts, and can be used as intermediates for the preparation and/or 4 purification of the compounds of the present invention and/or for the separation of enantiomers of the compounds of the present invention.
6 [00153] Furthermore, the compounds of the present invention, including their salts, may also be obtained in 7 the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present 8 invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water);
9 therefore, it is intended that the invention embrace both solvated and unsolvated forms.
PHARMACEUTICAL COMPOSITION OF THE COMPOUND OF THE INVENTION AND

12 [00154] The present invention relates to a pharmaceutical composition, which includes the compound of the 13 present invention or the compound of the structure shown in the examples, or a stereoisomer, a geometric isomer, a 14 tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, excipient, adjuvant, 16 vehicle or a combination thereof, and optionally, other therapeutic and/or prophylactic ingredients. In some 17 embodiments, the pharmaceutical composition disclosed herein comprises an effective amount of a compound 18 described herein and at least one pharmaceutically acceptable carrier, excipient, adjuvant or vehicle. The amount of 19 the compound in the pharmaceutical composition of the invention is effective to detectably agonize the thyroid hormone beta receptor in a biological specimen or patient.
21 [00155] Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the 22 biological activity of the compound. A pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, 23 non-inflammatory, non-immunogenic or otherwise free of adverse effects or side effects once administered to a 24 patient. Standard pharmaceutical techniques may be employed.
[00156] As described above, the pharmaceutical composition or pharmaceutically acceptable composition of 26 the present invention further comprises a pharmaceutically acceptable carrier, an excipient, an adjuvant or a vehicle, 27 which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, 28 surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and 29 the like, as suited to the particular dosage form desired. Remington:
The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical 31 Technology, eds. 1988-1999, Marcel Dekker, New York, discloses various carriers used in formulating 32 pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any 33 conventional carrier medium incompatible with the compounds disclosed herein, such as by producing any 34 undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, any other conventional carrier medium and its use is contemplated to be 36 within the scope of this invention.
37 [00157] Some examples of substances that can be used as pharmaceutically acceptable carriers include, but CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum 2 albumin), buffer substances (such as Tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial 3 glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate, 4 disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block 6 copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (such as lactose, glucose, and sucrose), 7 starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium 8 carboxymethylcellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gel, talc, excipients 9 (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate 11 and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, 12 pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffered saline and other nontoxic 13 compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and, at the discretion of the formulator, 14 colorants, detackifying agents, coating agents, sweetening and flavoring agents, preservatives and antioxidants can also be present in the compositions.
16 [00158] The pharmaceutical composition of the present invention can be administered directly or in the form 17 of a pharmaceutical composition or drug together with a suitable carrier or excipient, which is well known in the 18 art. The methods of treatment of the present invention may comprise administering to a subject in need thereof an 19 effective compound of the present invention. In some embodiments, the individual is a mammalian individual, in other embodiments, the individual is a human individual.
21 [00159] The effective amount of the compound, pharmaceutical composition or drug of the present invention 22 can be easily determined by conventional methods and tests, and the most effective and convenient route of 23 administration and the most suitable preparation can also be determined by conventional tests.
24 [00160] A compound or composition of the invention may be administered in any suitable means, and the above-mentioned compound and pharmaceutically acceptable composition can be administered to humans or other 26 animals by oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or 27 drops) or nasal spray according to the severity of the disease.
28 [00161] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically 29 acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluent commonly used in the art, such as, for example, water 31 or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl 32 acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in 33 particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, 34 polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening 36 agents, flavoring agents and fragrances.
37 [00162] Injectable preparations can be formulated according to known techniques using suitable dispersing CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. The sterile injectable 2 preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable 3 diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may 4 be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed 6 including synthetic monoglycerides or diglycerides. In addition, fatty acids such as octadecenoic acid are used in 7 the preparation of injectables.
8 [00163] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining 9 filter or by the addition of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
11 [00164] In order to prolong the effect of the compounds or compositions described herein, it is often desirable 12 to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished 13 by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of 14 absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is accomplished by 16 dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming 17 microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolic acid.
18 Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of 19 compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or 21 microemulsions that are compatible with body tissues.
22 [00165] Compositions for rectal or vaginal administration, in particular suppositories, may be prepared by 23 mixing a compound according to the invention with a suitable non-irritating excipient or carrier, such as cocoa 24 butter, polyethylene glycol or a suppository wax. The excipient or carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
26 [00166] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In 27 these dosage forms, the active compound of the present invention are mixed with at least one pharmaceutically 28 acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or bulking agents 29 such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerin; d) disintegrants such 31 as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) 32 solution retarders, such as paraffin; 0 absorption accelerators, such as quaternary ammonium compounds; g) 33 humectants, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) 34 lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
36 [00167] Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using 37 excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and 2 others well known in the pharmaceutical art. They may optionally contain opacifying agents and may also be of a 3 composition so that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, 4 optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
6 [00168] The active compounds can also be in microencapsulated form with one or more of the above-7 mentioned excipients. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, 8 such as sucrose, lactose or starch. In general, such dosage forms may also contain additional substances besides 9 inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also be of a composition so that they release the 11 active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner.
12 Examples of embedding compositions that can be used include polymeric substances and waxes.
13 [00169] Dosage forms for topical or transdermal administration of a compound of this invention include 14 unguents, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or 16 buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the 17 scope of this invention. Additionally, the present invention contemplates the use of skin patches with the added 18 advantage of providing controlled delivery of compounds to the body.
Such dosage forms can be made by dissolving 19 or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing 21 the compound in a polymer matrix or gel.
22 [00170] The compositions described herein may also be administered orally, parenterally, or topically, 23 rectally, nasally, buccally, vaginally by inhalation spray, or via an implanted kit. The term "parenteral" as used herein 24 includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the 26 compositions are administered orally, intraperitoneally or intravenously.
27 [00171] Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions.
28 These suspensions may be formulated following techniques known in the art using suitable dispersing or wetting 29 agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
31 Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium 32 chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
33 For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. In 34 addition, fatty acids such as octadecenoic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their 36 polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or 37 dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly 2 used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are 3 commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be 4 used for the purposes of formulation.
[00172] The pharmaceutical composition of the present invention can be orally administered in any orally 6 acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case 7 of tablets for oral administration, carriers commonly used include, but are not limited to, lactose and starch.
8 Lubricating agents, such as magnesium stearate, are also usually added.
For oral administration in a capsule form, 9 useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents.
Certain sweetening, flavoring or coloring 11 agents can also be added, if desired.
12 [00173] Alternatively, the pharmaceutical compositions described herein may be administered in the form of 13 suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing reagents with non-14 irritating excipients, such substances include but are not limited to cocoa butter, beeswax and polyethylene glycols.
[00174] The pharmaceutical compositions of the present invention may also be administered topically, 16 especially when the target of treatment includes topical instillation of easily accessible areas or organs, including 17 diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these 18 areas or organs.
19 [00175] Topical instillation to the lower intestinal tract can be achieved in rectal suppository formulations (see above) or in suitable enema formulations. Topical skin patches may also be used.
21 [00176] For topical administration, the pharmaceutical composition can be formulated as a suitable ointment 22 containing the active components suspended or dissolved in one or more carriers. Carrier compounds for topical 23 administration of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, 24 propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes and water. Alternatively, the pharmaceutical composition can be formulated in a suitable lotion or cream containing the active components 26 suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not 27 limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, 28 benzyl alcohol and water.
29 [00177] For ophthalmic use, the pharmaceutical composition is formulated as a micronized suspension in, or especially as a solution in, isotonic pH-adjusted sterile saline, with or without a preservative such as benzalkonium 31 chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment, such 32 as petrolatum.
33 [00178] The pharmaceutical compositions can also be administered by nasal aerosol spray or inhalation. Such 34 compositions are prepared according to techniques well known in the pharmaceutical art and solutions in saline are prepared using benzyl alcohol and other suitable preservatives, absorption enhancers to enhance bioavailability, 36 fluorocarbons and/or other conventional solubilizing or dispersing agents.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 [00179] The compound or pharmaceutical composition provided by the present invention can be used in the manufacture of a medicament for stimulating thyroid hormone receptors, or in the manufacture of a medicament for 3 preventing, treating or alleviating diseases regulated by thyroid hormone receptors.

[00180] The compound or pharmaceutical composition provided by the present invention can be used to stimulate thyroid hormone receptors, or to prevent, treat or alleviate diseases regulated by thyroid hormone 6 receptors.

[00181] The present invention relates to a method of stimulating thyroid hormone receptors or preventing, treating or alleviating diseases regulated by thyroid hormone receptors in a subject comprising administering a therapeutically effective amount of the above compound or its pharmaceutical composition to the subject in need.
Moreover, the above-mentioned compounds provided by the present invention or their pharmaceutical compositions can be co-administered with other therapies or therapeutic agents. The mode of administration can be carried out 12 simultaneously, sequentially or at certain time intervals.
13 [00182] The thyroid hormone receptor of the present invention is a thyroid hormone 0 receptor.

[00183] The diseases described in the present invention are nonalcoholic fatty liver diseases, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer, wherein the nonalcoholic fatty liver disease is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease-associated cryptogenic cirrhosis or primary liver 19 cancer.
[00184] The compound or pharmaceutical composition of the present invention can be used to treat fibrotic 21 diseases, including but not limited to liver fibrosis, idiopathic pulmonary fibrosis and the like.

[00185] Besides being useful for human treatment, these compounds are also useful for veterinary treatment 23 of animals such as companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
24 In other embodiments, the animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.

[00186] An "effective amount" or "effective dose" of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders. The compounds and pharmaceutically acceptable compositions are effective administered in a fairly wide dose range. For example, the daily dose is from about 0.1 mg to 1000 mg per person, the compounds or pharmaceutically acceptable compositions can be administered in a single dose or in several divided doses a day.

The compounds and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease.

The exact amount required will vary from subject to subject, depending on the species, age, and general condition 34 of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents as discussed above.

[00187] In order to describe the present invention, examples are listed below.
However, it should be CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 understood that the present invention is not limited to these examples, but only provides a method of practicing the 2 present invention.
3 [00188] In the present invention, if the chemical name of the compound doesn't match the corresponding 4 structure, the compound is characterized by the corresponding structure.
[00189] Generally, the compounds disclosed herein may be prepared by methods described herein, wherein 6 the substituents are as defined for Formula (I), except where further noted. The following non-limiting schemes and 7 examples are presented to further exemplify the invention.
8 [00190] Persons skilled in the art will recognize that the chemical reactions described may be readily adapted 9 to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified 11 compounds according to the invention may be successfully performed by modifications apparent to those skilled in 12 the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art 13 other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other 14 reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds disclosed herein.
16 [00191] The structures of the compounds were identified by nuclear magnetic resonance (111-NMR, I3C-17 NMR and/or '9F-NMR). 'H-NMR, '3C-NMR and/or '9F-NMR chemical shifts (8) were recorded as ppm (10-6). III-18 NMR, '3C-NMR and/or '9F-NMR were measured with Bruker Ultrashield-400 nuclear magnetic resonance 19 spectrometer and Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, and the measuring solvent was deuterated chloroform (CDC13), deuterated methanol (CD3OD or Me0H-d4) or deuterated dimethylsulfoxide 21 (DMSO-d6). TMS (0 ppm) or chloroform (7.25 ppm) was used as reference standards. When peak multiplicities are 22 reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiple , br 23 (broadened), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), td (triplet of 24 doublets), brs (broadened singlet). Coupling constant J, when given, was reported in Hertz (Hz).
[00192] Generally, Novasep pump 250 high-performance liquid chromatography was used for preparative 26 purification or preparative resolution.
27 [00193] LC-MS spectra were determined on Agilen-6120 Quadrupole LC/MS
mass spectrometer.
28 [00194] The silica gel used in column chromatography generally was Qingdao Ocean Chemical Factory 300 29 to 400 mesh silica gel.
[00195] The staring materials of the present invention were known or purchased from Shanghai Accela 31 Company, Energy Company, J&K, Alfa Company and the like, or they could be prepared by the conventional 32 synthesis methods in the prior art.
33 [00196] Unless otherwise stated, the reactions disclosed herein were carried out in a nitrogen atmosphere.
34 [00197] The term "nitrogen atmosphere" refers to such an atmosphere that a reaction flask was equipped with a balloon or a stainless steel autoclave filled with about 1 L nitrogen.
36 [00198] The term "hydrogen atmosphere" refers to such an atmosphere that a reaction flask was equipped 37 with a balloon or a stainless steel autoclave filled with about 1 L
hydrogen.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00199] Unless otherwise stated, the solution used in the examples disclosed herein was an aqueous solution.
2 [00200] Unless otherwise stated, the reaction temperature was room temperature.
3 [00201] Unless otherwise stated, the room temperature was from 20 C to 40 C.
4 [00202] The reaction process in the examples was monitored by thin layer chromatography (TLC). The solvent system for development of a TLC plate comprised dichloromethane and methanol, dichloromethane and 6 ethyl acetate, petroleum ether and ethyl acetate. The volume ratio of the solvents in the solvent system was adjusted 7 according to the polarity of the compounds.
8 [00203] The elution system of column chromatography comprised: A:
petroleum ether and ethyl acetate, B:
9 dichloromethane and ethyl acetate, C: dichloromethane and methanol. The volume ratio of the solvents in the elution system was adjusted according to the polarity of the compounds, and sometimes it was also adjusted by adding a 11 small amount of aqueous ammonia and acetic acid.
12 [00204] HPLC refers to High Performance Liquid Chromatography.
13 HPLC was determined on Agilent 1260 high pressure liquid chromatography spectrometer (chromatographic 14 column: Agilent ZORBAX Eclipse Plus C18 4.6mmx150mm, 3.5 pm);
The test condition of HPLC: the run time was 25 minutes (min); the column temperature was 35 C; the 16 detection was carried out at the wavelength of 210 nm and 245 nm;
17 [00205] the mobile phases were 0.05% phosphoric acid solution (A) and acetonitrile (B); and the flow rate 18 was 1.0 mL/min.
19 [00206] The mobile phase gradient is shown in Table A:
[00207] Table A
Time Gradient of mobile phase A Gradient of mobile phase B
0 min 90% 10%
15 min 10% 90%
20 min 10% 90%
min 90% 10%

22 [00208] The LC/MS/MS system used for the analysis in the biological test experiment included Agilent 1200 23 series vacuum degassing oven, binary syringe pump, orifice plate autosampler, column oven, Agilent G6430 triple 24 quadrupole mass spectrometer with electrospray ionization (ESI) source.
Quantitative analysis was carried out in 25 MRM mode, and the parameters of MRM conversion are shown in Table B:
26 [00209] Table B
Full scan 50-1400 Fragmentation voltage 230 V
Capillary voltage 55 V
Dryer temperature 350 C
Atomizer 0.28MPa CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 Dryer flow rate 10 L/min 2 [00210] An Agilent XDB-Cl 8, 2.1 x 30 mm, 3.5 gm column was used for analysis, and 5 ELL of the sample 3 was injected. Analytical conditions: Mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in 4 methanol (B). The flow rate was 0.4 mL/min. The mobile phase gradient is shown in Table C:
[00211] Table C
Time Gradient of mobile phase B
0.5 min 5%
1.0 min 95%
2.2 min 95%
2.3 min 5%
5.0 min Termination 7 [00212] Low-resolution mass spectral (MS) data were determined on an Agilent 6120 Quadrupole HPLC-8 MS spectrometer equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 3.5 gm). The flow rate was 0.6 mL/min;
9 the mobile phases consisted of a combination of A (0.1% formic acid in CH3CN) and B (0.1% formic acid in H20) in gradient mode (5% to 95%), and an ESI source was used, the peak of HPLC was recorded with UV-Vis detection 11 at 210 nm/254 nm.

13 [00213] The following abbreviations are used throughout the specification:
DMSO-d6: Deuterated DMSO:
Dimethylsulfoxide;
dimethylsulfoxide;
TFA: Trifluoroacetic acid; mL, ml:
Milliliter;
II, IA: Microliter; mol/L, mo1/1:
Mole/liter;
mol: Moore; mmol/L, mmo1/1, mM:
Millimol/L;
gmol/L, gmo1/1, gM: Micromon; nmol/L, nmo1/1, nM:
Nanomol/L;
g: Gram; h: Hour;
mg: Milligram; gg:
Microgram;
ng: Nanogram; %wt, mass%: % by weight;
gm: Micron; MPa:
Megapascal;
min: Minute; ACN:
Acetonitrile;
Me: Methyl; Et Ethyl;

[00214] Typical synthetic procedures for the preparation of the compounds disclosed herein are shown in the
16 following synthetic schemes. Unless otherwise stated, each ring A, R', R3a, R3b, R3c and R3d have the definitions as
17 described in the present invention, and X is halogen.
18 Synthesis scheme 1:

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 R3d X k ,R3c 00 ,(OH ^ Dt,,r-i R3d R3d R3d N )1:)'=
.38 NO2 R3, Ri H 0 R3c (I-b) R3b 0 R3c 0 0 0 -'=- n ,N,7õ1-1õ ..---....

N'Ll'O -GO R3a NO2 R3b R3b (I-a) (I-c) (I-d) 0-R3d c OõõO 0 ____________________ ' A
R3a ' N 1 NH
R3b N o 1 (I-A) R1 2 [00215] The compound with the structure shown in general formula (I-A) can be prepared by the general 3 synthesis method described in synthesis scheme 1, and the specific steps can be referred to the examples. First, 4 compound (I-a) can be reacted with compound (I-b) under the action of a base (such as potassium carbonate) to obtain compound (I-c); compound (I-c) can be reduced by nitro to obtain compound (I-d); compound (I-d) can be 6 diazotized with the amino group and reacted with compound (I-e) to obtain compound (I-f); compound (I-f) can be 7 ring-closed under the action of a base (such as sodium acetate) to obtain the target compound represented by general 8 formula (I-A).
9 Synthesis scheme 2:
13(1 13d R3d 0, R3 I )- -'"
Oa 1 N NH R3a 1 N NH
R3b IV R3b N R3b N
J.

(II-a) ON (II-b) COOH (I-B) 11 [00216] The compound with the structure shown in general formula (I-B) can be prepared by the general 12 synthesis method described in synthesis scheme 2, and the specific steps can be referred to the examples. First, 13 compound (II-a) can be hydrolyzed under acidic conditions (such as concentrated hydrochloric acid) to obtain 14 compound (11-b); compound (11-b) can be decarboxylated to obtain the target compound represented by general formula (1-B).
16 Example 17 Example 1 2-(3,5-diehloro-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-3/Boxy)pheny1)-3,5-dioxo-2,3,4,5-18 tetrahydro-1,2,4-biazine-6-carbonitrile 1 ci . , a a a ,-- , ,, ,OH )1 =' .j), 0 .-, .0 ).
CI NO2 \ \
V
Step 1 HN HN 7 CIA ,ANH, CI1' V NO2 Step 2 Step 3 H
CIN H

la lb 1d ld ____________________ . HIV.1C7 T5, Step 4 '7 Cl' N NH
0 A,
19 CN
Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00217] To a solution of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one la (1.00 g, 6.13 mmol) and 1,2,3-2 trichloro-5-nitrobenzene (1.39 g, 6.14 mmol) in N,AT-dimethylformamide (10 mL) was added potassium carbonate 3 (2.14 g, 15.3 mmol), and the mixture was reacted at 120 C for 16 hours.
The reaction solution was cooled to room 4 temperature, then water (20 mL) was added. The reaction mixture was stirred for 15 minutes and filtered to collect filter cake. The filter cake was recrystallized with ethanol/ethyl acetate/petroleum ether (1/2/4, 35 mL), and filtered 6 to collect filter cake. After drying, a yellow solid lb (1.41 g, yield 65%) was obtained.
7 MS (ESL, pos. ion) m/z: 353.1 [M+H]t 8 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lc 9 [00218] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.4 g, 4.0 mmol) in acetic acid (8 mL) was added iron powder (0.22 g, 3.9 mmol), and the mixture was reacted at 70 C for 2 11 hours. The reaction solution was cooled to room temperature, iron powder was removed, then water (30 mL) was 12 added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was 13 collected and dried to obtain a yellow solid lc (1.0 g, yield 78%).
14 MS (ESL, pos. ion) m/z: 323.2 [M+H]t Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-16 yl)oxy)phenyl)hydrazono)acetyl)carbamate ld 17 [00219] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lc (0.20 g, 18 0.62 mmol) and N-cyanoacetylurethane (0.11 g, 0.69 mmol) in acetic acid (4 mL) was added a solution of sodium 19 nitrite (65 mg, 0.93 mmol) in water (2 mL) at 0 C, and the mixture was reacted for 4.5 hours. At 0 C, water (10 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (2 mL), 21 and the filter cake was collected and dried to obtain an orange solid ld (0.30 g, yield 99%).
22 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-23 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 24 [00220] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyphydrazono)acetyl)carbamate ld (0.30 g, 0.61 mmol) in N,N-dimethylformamide (3 mL) was added 26 sodium acetate (55 mg, 0.67 mmol), and the mixture was reacted at 120 C
for 5 hours. The reaction solution was 27 cooled to room temperature, water (20 mL) was added, solid was precipitated out. The mixture was stirred for 10 28 minutes, filtered, and rinsed with water (5 mL). The filter cake was collected and dried, and the obtained reddish-29 brown solid was recrystallized (acetonitrile/ethanol/ N,N-dimethylformamide/water=10/5/2/20, 37 mL), filtered, and rinsed with water (2 mL). The filter cake was collected and dried to obtain an orange solid 1 (0.13 g, yield 48%, 31 purity 91.86%).
32 MS (ESL, neg. ion) m/z: 442.0 [M-H]-.
33 11-1 NMR (400 MHz, DMSO-d6) (ppm) 13.27 (s, 1H), 7.85 (d, J= 6.4 Hz, 4H), 6.87 (s, 1H), 6.81 (dd,J=
34 8.6, 2.3 Hz, 1H), 3.32 (s, 2H), 2.90 (t, J= 6.2 Hz, 2H).
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Example 2 2-(3,5-diehloro-4-((2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2 2,3,4,5-tetrahydro-1,2,44tiazine-6-carbonitrile 2 0 t I ci)oN n C NH2 0 0 HN, 7 Step 1 õ. NO2No, Step 2 lnStep a No2 0 lb 0 2, 0 2h 20 CI
(36, )13 N
¨ H
Step 4 CI

4 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-methy1-3,4-dihydroisoquinolin-1(2H)-one 2a [00221] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.0 g, 2.8 6 mmol) in THF (15 mL) were added sodium hydride (0.23 g, 5.8 mmol, 60% in oil) and methyl iodide (0.26 mL, 4.2 7 mmol), and the mixture was reacted at room temperature for 2.5 hours. The reaction was quenched with water (10 8 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with 9 saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give a yellow 11 solid 2a (1.0 g, yield 99%).
12 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-methy1-3,4-dihydroisoquinolin-1(2H)-one 2b 13 [00222] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-methy1-3,4-dihydroisoquinolin-1(211)-one 2a 14 (1.0 g, 2.7 mmol) in acetic acid (8 mL) was added iron powder (0.30 g, 5.4 mmol), and the mixture was reacted at 70 C. The reaction solution was cooled to room temperature, iron powder was removed, then water (30 mL) was 16 added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was 17 collected and dried, and the obtained solid was purified by silica gel column chromatography (petroleum ether/ethyl 18 acetate = 1/1) to obtain a yellow solid 2b (0.40 g, yield 44%).
19 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-methyl-l-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyphydrazono)acetyl)carbamate 2c 21 [00223] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-methy1-3,4-dihydroisoquinolin-1(2H)-one 2b 22 (0.40 g, 1.2 mmol) and N-cyanoacetylurethane (0.21 g, 1.3 mmol) in acetic acid (8 mL) was added a solution of 23 sodium nitrite (0.17g, 2.4 mmol) in water (4 mL) at 0 C, and the mixture was reacted for 4 hours. At 0 C, water (10 24 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (2 mL), and the filter cake was collected and dried to obtain a red solid 2c (0.62 g, yield 99%).
26 Step 4: Synthesis of 2-(3,5-dichloro-44(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-27 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2 28 [00224] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-methyl-1-oxo-1,2,3,4-29 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 2c (0.62 g, 1.2 mmol) in N,N-dimethylformamide (6 mL) was added sodium acetate (0.11 g, 1.3 mmol), and the mixture was reacted at 120 C for CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 6 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was 2 extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with saturated sodium chloride 3 solution (40 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue 4 was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/3), and the obtained solid was recrystallized (acetonitrile/ethyl acetate/ethanol/petroleum ether=3/10/15/30, 58 mL) to obtain a light red solid 2 6 (0.21 g, yield 38%, purity: 97.61%).
7 MS (ESL, neg. ion) m/z: 456.0 [M-H];
8 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 111), 8.11-7.63 (m, 311), 6.91-6.76 (m, 2H), 3.53 (t, J= 6.6 9 Hz, 2H), 3.00 (s, 3H), 2.97 (t, J= 6.6 Hz, 2H).
Example 3 2-(3,5-dichloro-44(2-(methoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-11 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3 oi FinWN-1 NH r' CI -N NH

y 0 CN
13 [00225] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-14 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.10 g, 0.23 mmol) in methanol (4 mL) was added 37%
formaldehyde (0.37 mL, 5.0 mmol). The mixture was sealed and reacted at 100 C
for 16 hours. The reaction solution 16 was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel column 17 chromatography (petroleum ether/ethyl acetate = 1/1), and the obtained solid was recrystallized (methanol/ethyl 18 acetate/petroleum ether = 1/6/12, 9.5 mL) to obtain a white solid 3 (50 mg, yield 45%, HPLC purity: 97.51%).
19 MS (ESL, neg. ion) m/z: 486.0 [M-1-1]-;
NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.91 (d, J= 8.6 Hz, 1H), 7.84 (s, 2H), 6.95-6.81 (m, 21 2H), 4.86 (s, 2H), 3.56 (t, J= 6.4 Hz, 2H), 3.22 (s, 3H), 2.98 (t, J=
6.2 Hz, 2H).
22 Example 4 2-(3,5-dichloro-44(2-(ethoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-23 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 4 ci HN
CI N ONNNH

CN
[00226] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-26 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.40 g, 0.90 mmol) in ethanol (10 mL) was added 37%
27 formaldehyde (2.0 mL, 27 mmol). The mixture was sealed and reacted at 100 C for 48 hours. The reaction solution 28 was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel column 29 chromatography (petroleum ether/ethyl acetate = 1/1), and the obtained solid was recrystallized (ethanol/ethyl CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 acetate/petroleum ether = 1/5/3, 18 mL) to obtain a white solid 4 (0.28 g, yield 62%, HPLC purity: 96.19%).
2 MS (ESL, neg. ion) m/z: 500.0 [M-11]-;
3 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 1H), 8.06-7.74 (m, 3H), 6.99-6.74 (m, 211), 4.90 (s, 2H), 4 3.56 (t, J= 6.1 Hz, 2H), 3.49-3.43 (m, 2H), 2.98 (t, J= 5.8 Hz, 2H), 1.11 (t, J= 6.9 Hz, 3H).
Example 5 2-(3,5-dichloro-4-02-ethyl-l-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylloxylpheny1)-3,5-dioxo-6 2,3,4,5-tetrahydro-1,2,44tiazine-6-carbonitrile 5 [ , -Step 1 ----.1-'5/1-1L'"j Step 2 Step Step 4 '-1.1%.,2 6a 6b CI 6c 5d GI
CI
Nrj Step 5 7r11 Ni_,]C%11) Step ID ;
i'N1 II NH

6f 8 Step 1: Synthesis of 2-ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 5b 9 [00227] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (2.05 g, 11.6 mmol) was dissolved in a mixture solution of THF (40 mL) and N,N-dimethylacetamide (15 mL). Sodium hydride (0.58 g, 14.5 mmol, 60% in oil) 11 was added in portions at 0 C, then ethyl iodide (1.13 mL, 13.8 mmol) was added dropwise, and the mixture was 12 reacted at 50 C for 24 hours. The reaction solution was cooled to room temperature, quenched by the addition of 13 ice water (40 mL), and then concentrated in vacuo to remove tetrahydrofuran. The remaining solution was extracted 14 by ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride (45 mL ><
3), dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel 16 column chromatography (petroleum ether/ethyl acetate = 3/1) to give light yellow oil 5b (2.30 g, yield 97%).
17 MS (ESL, pos. ion) m/z: 206.2 [M+H].
18 Step 2: Synthesis of 2-ethy1-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one Sc 19 [00228] 2-Ethyl-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 5b (2.40 g, 11.7 mmol) was dissolved in dichloromethane (50 mL). Boron tribromide (2.28 mL, 23.4 mmol) was slowly added dropwise at 0 C and the 21 mixture was continued stirring for 3.5 hours. The reaction was quenched by slowly adding methanol (10 mL) 22 dropwise at 0 C. The mixture was concentrated in vacuo, extracted with ethyl acetate (40 mL >< 3). The combined 23 organic layers werewashed with saturated sodium chloride solution (40 mL
>< 2), dried over anhydrous sodium 24 sulfate, and concentrated by suction filtration to give a brown-yellow solid Sc (2.01 g, yield 90%).
MS (ESL, neg. ion) m/z: 190.1 [M-H]-.
26 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-ethy1-3,4-dihydroisoquinolin-1(21I)-one 5d 27 [00229] To a solution of 2-ethy1-6-hydroxy-3,4-dihydroisoquinolin-1(211)-one Sc (2.00 g, 10.5 mmol) in N,N-28 dimethylacetamide (25 mL) were added 1,2,3-trichloro-5-nitrobenzene (2.37 g, 10.5 mmol) and potassium 29 carbonate (5.61 g, 40.2 mmol) in sequence, and the mixture was reacted at 80 C for 7 hours. The reaction solution CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 was cooled to room temperature, poured into water (50 mL), stirred for 20 minutes, then hydrochloric acid (3 N, 15 2 mL) was added dropwise. The reaction mixture was filtered, the solid was collected and dried, and the obtained 3 solid was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain a white solid 4 5d (3.42 g, yield 86%).
MS (ESI, pos. ion) m/z: 381.0 [M+H]t 6 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-ethy1-3,4-dihydroisoquinolin-1(211)-one 5e 7 [00230] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-ethy1-3,4-dihydroisoquinolin-1(211)-one 5d 8 (2.05 g, 5.38 mmol) in acetic acid (25 mL) was added iron powder (1.23 g, 21.6 mmol), and the mixture was reacted 9 at 60 C for 4 hours. The reaction solution was cooled to room temperature, iron powder was removed, then water (50 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The 11 filter cake was collected and dried to obtain a yellow solid 5e (1.80 g, yield 95%).
12 MS (ESL, pos. ion) m/z: 351.1 [M+H]t 13 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-ethyl-l-oxo-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)phenyl)hydrazono)acetyl)carbamate 51 [00231] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-ethy1-3,4-dihydroisoquinolin-1(211)-one 5e 16 (0.80 g, 2.28 mmol) and N-cyanoacetylurethane (0.40 g, 2.50 mmol) in acetic acid (15 mL) was added a solution of 17 sodium nitrite (0.24 g, 3.42 mmol) in water (2 mL) at 0 C, and the mixture was reacted for 3 hours. At 0 C, water 18 (35 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (10 19 mL), and the filter cake was collected and dried to obtain a yellow solid 5f (1.10 g, yield 93%).
MS (ESL, neg. ion) m/z: 515.9 [M-H].
21 Step 6: Synthesis of 2-(3,5-dichloro-44(2-ethyl-l-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-22 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 5 23 [00232] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-ethyl- 1 -oxo-1,2,3,4-tetrahydroisoquinolin-24 6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 5f (1.10 g, 2.12 mmol) in N,N-dimethylformamide (25 mL) was added sodium acetate (0.88 g, 12.9 mmol), and the mixture was reacted at 120 C
for 6 hours. The reaction solution 26 was cooled to room temperature. The reaction solution was poured into water (100 mL), stirred for 30 minutes, 27 filtered, the filter cake was collected and dried, and the obtained pale yellow solid was separated and purified by 28 pre-HPLC [50%ACN/50%H20 (0.1% TFA), Kromasil Specifications: C18 1 Opmx5Ommx 250mm, flow rate: 100 29 mL/min] to obtain a white solid 5 (0.56 g, yield 54%, HPLC purity:
99.80%).
MS (ESL, neg. ion) m/z: 470.0 [M-H];
31 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 13.29 (s, 1H), 7.92-7.81 (m, 3H), 6.82 (dd, J = 13.1, 4.5 Hz, 2H), 32 3.55-3.50 (m, 2H), 3.50-3.45 (m, 2H), 2.95 (t, J= 6.4 Hz, 2H), 1.10 (t, J= 7.1 Hz, 311).
33 Example 6 Methyl 2-(3,5-dichloro-4-((2-methy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)phenyl)-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 6 o o -N-c- CI - N NH CI - N NH
2 2 CN 6 COOMe 3 [00233] 243,5 -Dichloro-442 -methyl-1 -oxo-1,2,3,4-tetmhydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-4 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 2 (0.30 g, 0.66 mmol) was dissolved in a methanol solution of hydrogen chloride (10 mL, 40 mmol, 4.0 mol/L). The mixture was reacted at 70 C
for 48 hours. The reaction 6 solution was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum 7 ether/ethyl acetate = 1/4) to obtain a light yellow solid 6 (35 mg, yield 11%, HPLC purity: 98.29%).
8 MS (ESI, pos. ion) m/z: 492.00 [M+H];
9 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 7.87 (d, J= 8.7 Hz, 3H), 6.87-6.76 (m, 2H), 4.13 (d, J= 5.0 Hz, 1H), 3.85 (s, 311), 3.52 (t, J= 6.6 Hz, 2H), 3.17 (d, J= 4.1 Hz, 311), 2.97 (t, J=
6.7 Hz, 2H).
11 Example 7 2-(3,5-Dichloro-441-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azepin-7-ylloxylpheny1)-3,5-dioxo-12 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7 I Step 1 2 I I
H/NI I CI <- NH2 SteP

HN -Cl- NOS2teP
0 7a 0 7b 0 7c 0 CN
CI 7d Step 4 HN -( CI 'N¨NH

14 Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-l-one 7b [00234] To a solution of 7-hydroxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin- 1 -one 7a (0.60 g, 3.4 mmol) and 16 1,2,3-trichloro-5-nitrobenzene (0.77 g, 3.4 mmol) in /V,N-dimethylformamide (8 mL) was added potassium 17 carbonate (1.2 g, 8.6 mmol), and the mixture was reacted at 120 C for 16 hours. The reaction solution was cooled 18 to room temperature, then water (10 mL) was added. The reaction mixture was stirred for 15 minutes and filtered.
19 The collected filter cake was slurried with ethanol/ethyl acetate/petroleum ether (1/2/4, 28 mL), and filtered to collect filter cake. After drying, a brown solid 7b (0.90 g, yield 72%) was obtained.
21 Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo [c] azepin-1 -one 7c 22 [00235] To a solution of 7-(2,6-dichloro-4-nitrophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 7b 23 (0.50 g, 1.4 mmol) in acetic acid (5 mL) was added iron powder (91 mg, 1.63 mmol), and the mixture was reacted 24 at 70 C for 2 hours. The reaction solution was cooled to room temperature, iron powder was removed, then water (48 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The 26 solid was collected and dried to obtain a yellow solid 7c (0.36 g, yield 78%).
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-2 yl)oxy)phenyphydrazono)acetyl)carbamate 7d 3 [00236] To a solution of 7-(4-amino-2,6-dichlorophenoxy)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1 -one 7c 4 (0.26 g, 0.77 mmol) and N-cyanoacetylurethane (0.14 g, 0.88 mmol) in acetic acid (8 mL) was added a solution of sodium nitrite (0.11 g, 1.6 mmol) in water (4 mL) at 0 C, and the mixture was reacted for 2 hours. At 0 C, water 6 (10 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (2 7 mL), and the filter cake was collected and dried to obtain a yellow solid 7d (0.39 g, yield 100%).
8 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2,3,4,5-tetrahydro-2H-benzo[c]azepin-7-yl)oxy)pheny1)-3,5-9 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 7 [00237] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1 -oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-11 7-yl)oxy)phenyl)hydrazono)acetyl)carbamate 7d (0.39 g, 0.77 mmol) in N,N-dimethylformamide (4 mL) was added 12 sodium acetate (70 mg, 0.85 mmol), and the mixture was reacted at 120 C
for 5 hours. The reaction solution was 13 cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 14 5). The combined organic layers were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column 16 chromatography (100% ethyl acetate), and the obtained solid was recrystallized (ethanol/ethyl acetate/petroleum 17 ether=1/5/6, 12 mL) to obtain a reddish-brown solid 7 (26 mg, yield 7.3%, HPLC purity: 82.24%).
18 MS (ESL, neg. ion) m/z: 456.5 [M-H]-;
19 111 NMR (400 MHz, DMSO-d6) 5 (ppm) 7.99 (t, J= 5.7 Hz, 1H), 7.84 (s, 2H), 7.51 (d, J= 8.5 Hz, 1H), 6.87 (d, J= 2.4 Hz, 1H), 6.76 (dd, J= 8.5, 2.5 Hz, 1H), 2.97-2.89 (m, 2H), 2.74 (t, J= 6.9 Hz, 2H), 1.93-1.81 (m, 2H).
21 Example 8 2-(3,5-dichloro-4-42-oxo-1,2,3,4-tetrahydroquinolin-7-ylloxylpheny1)-3,5-dioxo-2,3,4,5-22 tetrahydro-1,2,4-triazine-6-carbonitrile 8 CI CI

0 1,1 ____________________________ - ;0-H Step 1 N ,NO2 Step z Step 3 CI

ea 88 80 ed NHCOOEt CI 0 01 Oy.ki I
Step 4 NH
CN

24 Step 1: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroquinolin-2(1H)-one 8b [00238] To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one 8a (1.20 g, 7.35 mmol) in N,N-26 dimethylformamide (15 mL) were added 1,2,3-trichloro-5-nitrobenzene (1.67 g, 7.38 mmol) and potassium 27 carbonate (2.46 g, 17.6 mmol), and the mixture was reacted at 80 C for 4 hours. The reaction solution was cooled 28 to room temperature, then poured into water (50 mL). The reaction mixture was stirred for 30 minutes, filtered, and 29 the filter cake was collected and dried to obtain a light yellow solid 8b (2.46 g, yield 95%).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 MS (ESI, neg. ion) m/z: 351.0 [M-H].
2 Step 2: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroquinolin-2(1H)-one Sc 3 1002391 To a solution of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroquinolin-2(1H)-one 8b (2.00 g, 5.66 4 mmol) in acetic acid (40 mL) was added iron powder (1.29 g, 22.6 mmol), and the mixture was reacted at 60 C for 4.5 hours. The reaction solution was cooled to room temperature, iron powder was removed, then water (100 mL) 6 was added dropwise. The reaction mixture was stirred for 30 minutes, and filtered. The filter cake was collected and 7 dried to obtain a light gray solid 8c (1.71 g, yield 93%).
8 MS (ESL, pos. ion) m/z: 323.0 [M+H]t 9 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyphydrazono)acetyl)carbamate 8d 11 [00240] To a solution of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroquinolin-2(1H)-one 8c (0.70 g, 2.17 12 mmol) and N-cyanoacetylurethane (0.38 g, 2.39 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite 13 (0.23 g, 3.25 mmol) in water (3 mL) at 0 C, and the mixture was reacted for 3 hours. At 0 C, water (20 mL) was 14 added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (4 mL), and the filter cake was collected and dried to obtain a yellow solid 8d (0.88 g, yield 83%).
16 MS (ESL, neg. ion) m/z: 488.1 [M-H].
17 Step 4: Synthesis of 2-(3,5-dichloro-44(2-oxo-1,2,3,4-tetrahydroquinolin-7-ypoxy)pheny1)-3,5-dioxo-18 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 8 19 [00241] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy)phenyphydrazono)acetyl)carbamate 8d (0.85 g, 1.73 mmol) in N,N-dimethylformamide (10 mL) was added 21 sodium acetate (0.72 g, 8.65 mmol), and the mixture was reacted at 120 C
for 6 hours. The reaction solution was 22 cooled to room temperature, then water (40 mL) was added. The reaction mixture was stirred for 10 minutes, then 23 hydrochloric acid (2 N, 3 mL) was added. The mixture was stirred for 10 minutes, filtered, and the filter cake was 24 collected and dried to obtain a gray solid 8 (0.56 g, yield 73 %, HPLC
purity: 89.58%).
MS (ESL, neg. ion) m/z: 442.1 [M-H];
26 11-1 NMR (600 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 9.98 (s, 1H), 7.82 (s, 2H), 7.14 (d, J= 8.3 Hz, 1H), 27 6.44 (dd, J= 8.2, 2.6 Hz, 1H), 6.40 (d, J= 2.5 Hz, 1H), 2.83 (t, J= 7.5 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H).
28 Example 9 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-29 tetrahydro-1,2,4-biazine-6-carbonitrile 9 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 o, OH 0 CI

-II
Step 1 Step 2 I
CI

Step 3 9a 9b 9c 9d _______________________ HN N 5,) H5 r\ I Cj)t Step 4 CI N N Step CI' N7 NH

9e 9 2 Step 1: Synthesis of 7-hydroxy-3,4-dihydroisoquinolin-1(211)-one 9b [00242] At 0 C, to a solution of 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one 9a (5.0 g, 28 mmol) in dichloromethane (30 mL) was added boron tribromide (5.5 mL, 57 mmol) dropwise.
The reaction was continued for 3.5 hours. The reaction solution was poured into ice water (40 mL) to quench the reaction. The mixture was stirred for 30 minutes, and filtered. The filter cake was washed with water (5 mL x 2) and dried. The obtained solid was recrystallized (ethanol/ethyl acetate/petroleum ether= 1/3/3, 42 mL) to give a brown solid 9b (5.0 g, yield 8 100%).
9 Step 2: Synthesis of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9c [00243] To a solution of 7-hydroxy-3,4-dihydroisoquinolin-1(211)-one 9b (1.5 g, 9.2 mmol) and 1,2,3-trichloro-5-nitro-benzene (2.3 g, 10 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (2.6 12 g, 19 mmol), and the mixture was reacted at 80 C for 4 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added. The reaction mixture was stirred for 15 minutes and filtered. The filter cake was collected to obtain a yellow solid. The collected filter cake was slurried with ethanol/ethyl acetate/petroleum ether (1/3/6, 50 mL), and filtered to collect filter cake. After drying, a gray solid 9c (2.4 g, yield 74%) was obtained.
16 Step 3: Synthesis of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9d [00244] To a solution of 7-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9c (2.4 g, 6.8 mmol) in acetic acid (15 mL) was added iron powder (1.5 g, 3.9 mmol), and the mixture was reacted at 70 C for 3 hours. The reaction solution was cooled to room temperature, iron powder was removed, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The solid was 21 collected and dried to obtain a white solid 9d (1.00 g, yield 46%).

Step 4: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((l-oxo-1,2,3,4-tetrahydroisoquinolin-7-23 yl)oxy)phenyl)hydrazono)acetyl)carbamate 9e [00245] To a solution of 7-(4-amino-2,6-dichlorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 9d (0.20 g, 0.62 mmol) and N-cyanoacetylurethane (0.11 g, 0.69 mmol) in acetic acid (4 mL) was added a solution of sodium nitrite (65 mg, 0.93 mmol) in water (2 mL) at 0 C, and the mixture was reacted for 3.5 hours. At 0 C, water (10 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (2 mL), 28 and the filter cake was collected and dried to obtain a yellow solid 9e (0.30 g, yield 99%).

Step 5: Synthesis of 2-(3,5-dichloro-4-((1 -oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)pheny1)-3,5-dioxo-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 9 [00246] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yBoxy)phenyphydrazono)acetyl)carbamate 9e (0.30 g, 0.61 mmol) in N,N-dimethylformamide (4 mL) was added sodium acetate (55 mg, 0.67 mmol), and the mixture was reacted at 120 C for 5 hours. The reaction solution was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (100 mL
6 x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was recrystallized (ethanol/ethyl 8 acetate/petroleum ether=1/7/11, 19 mL) to obtain an off-white solid 9 (0.18 g, yield 66%, HPLC purity: 98.20%).
9 MS (ESL, neg. ion) m/z: 442.0 [M-H]-;
'11 NMR (600 MHz, DMSO-d6) 13 (ppm) 13.30 (s, 1H), 8.06 (s, 1H), 7.85 (s, 2H), 7.35 (d, J= 8.4 Hz, 1H), 11 7.16 (dd, J= 8.3, 2.8 Hz, 1H), 7.09 (d, J= 2.8 Hz, 1H), 3.36 (d, J= 2.3 Hz, 2H), 2.87 (t, J= 6.5 Hz, 2H).
12 Example 10 2-(3,5-Dichloro-44(2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-13 yl)oxylpheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazhie-6-earbonitrile 10 CI
,OBn ri--1013n I OHeHStep 1 FIN Step 2 Step 3 1 Step 4 '0- 01) NO2 la 10b 100 10d 10a CI
. O. X
11;' TC), Step 5 ---.0,N.11; NH, Step 6 01" NH 0 Step 7 'N'tf CI N
NH
0 Nyll'NHCOOEt 10e 10f 10 Step 1: Synthesis of 6-(benzyloxy)-3,4-dihydroisoquinolin-1(211)-one 10a [00247] To a solution of 6-hydroxy-3,4-dihydroisoquinolin-1(211)-one la (5.0 g, 31 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (6.4 g, 46 mmol). The mixture was reacted at room temperature for 15 minutes, benzyl bromide (4.4 mL, 37 mmol) was added dropwise, and the mixture was reacted 19 at room temperature for 48 hours. Water (100 mL) was added to quench the reaction. The reaction mixture was stirred for 20 minutes, and filtered. The solid was collected and dried to obtain a white solid 10a (6.2 g, yield 80%).
21 Step 2: Synthesis of 6-(benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10b [00248] 6-(Benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 10a (3.0 g, 12 mmol) was dissolved in a mixture solution of TI-IF (24 mL) and N,N-dimethylformamide (6 mL). Sodium hydride (1.4 g, 35 mmol, 60% in oil) was added. The mixture was reacted at room temperature for 15 minutes. Then 1-bromo-2-methoxy-ethane (1.7 mL, 18 mmol) was added dropwise, and the mixture was reacted at 60 C for 4 hours. The reaction was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction 28 filtration to give yellow oil 10b (3.7 g, 100% yield).
29 Step 3: Synthesis of 6-hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(21/)-one 10c [00249] 6-(Benzyloxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(211)-one 10b (3.7 g, 12 mmol) was CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 dissolved in ethanol (30 mL), and 10% palladium carbon (0.37 g) was added. The reaction mixture was degassed 2 and refilled with hydrogen (3 MPa), and hydrogenation was carried out for 16 hours. The reaction solution was 3 filtered, and the filtrate was collected and concentrated to obtain a yellow solid 10c (2.6 g, yield 99%).
4 Step 4: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10d 6 [00250] To a solution of 6-hydroxy-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one 10c (0.50 g, 2.3 7 mmol) and 1,2,3-trichloro-5-nitro-benzene (0.56 g, 2.5 mmol) in /V,N-dimethylformamide (5 mL) was added 8 potassium carbonate (0.63 g, 4.5 mmol), and the mixture was reacted at 70 C for 3 hours. The reaction solution was 9 cooled to room temperature, then water (10 mL) was added. The reaction mixture was stirred for 15 minutes and filtered to collect filter cake. The filter cake was recrystallized (ethyl acetate/petroleum ether = 3/5, 12 mL) to obtain 11 a yellow solid 10d (0.49 g, yield 53%).
12 Step 5: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-13 one 10e 14 [00251] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(211)-one 10d (0.40 g, 0.97 mmol) in acetic acid (4 mL) was added iron powder (0.14 g, 2.48 mmol), and the 16 mixture was reacted at 60 C for 5 hours. The reaction solution was cooled to room temperature, then water (12 mL) 17 was added to quench the reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water 18 (20 mL). The solid was collected and dried to obtain an off-white solid 10e (0.33 g, yield 89%).
19 Step 6: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 10f 21 [00252] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-22 1(210-one 10e (0.33 g, 0.87 mmol) in acetic acid (6.6 mL) was added a solution of sodium nitrite (90 mg, 1.29 23 mmol) in water (3.3 mL) at 0 C. The mixture was reacted for 10 minutes, then N-cyanoacetylurethane (0.17 g, 1.1 24 mmol) was added, and the reaction was continued at 0 C for 1 hour. At 0 C, water (12 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (10 mL), and the filter cake was 26 collected and dried to obtain a yellow solid 10f (0.47 g, yield 99%).
27 Step 7: Synthesis of 2-(3,5-dichloro-44(2-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-28 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 10 29 [00253] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(2-methoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 10f (0.47 g, 0.86 mmol) in N,N-31 dimethylformamide (3 mL) was added sodium acetate (0.77 g, 0.94 mmol), and the mixture was reacted at 120 C.
32 The reaction solution was cooled to room temperature, then water (10 mL) was added. The reaction mixture was 33 stirred for 10 minutes and filtered. The collected solid was recrystallized (ethanol/ethyl acetate/petroleum ether =
34 7.5/20/10, 37.5 mL), and filtered to collect filter cake. After drying, an off-white solid 10 (0.23 g, yield 53%, HPLC
purity:96.55%) was obtained.
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 MS (ESL neg. ion) m/z: 500.1 [M-1-1]-;

1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.28 (s, 1H), 7.86 (d, J= 12.5 Hz, 3H), 6.82 (d, J= 10.8 Hz, 2H), 3 3.61 (d, J= 5.3 Hz, 2H), 3.59-3.54 (m, 2H), 3.52-3.49 (m, 2H), 3.26 (s, 3H), 2.93 (t, J= 5.7 Hz, 2H).

Example 11 Methyl 2-(3,5-dichloro-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate 11 CI CI
H ry0 01-c)1NNH
") 9 iscyl NH HN
N

COOMe 7 [00254] To 2-(3,5-dichloro-4-((1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.10 g, 0.23 mmol) was added a solution of hydrogen chloride in methanol (5 mL, 4.5 mol/L). The mixture was reacted at 70 C for 24 hours. The reaction solution was cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (100%
11 ethyl acetate) to obtain a white solid 11 (45 mg, yield 42%, HPLC
purity: 95.69%).
12 MS (ESL pos. ion) m/z: 477.0 [M+Hr;

1 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.79 (s, 1H), 7.86 (s, 3H), 7.84 (s, 1H), 6.87 (d, J= 2.2 Hz, 1H), 14 6.81 (dd, J= 8.6, 2.5 Hz, 1H), 3.85 (s, 3H), 3.45 (d, J= 9.4 Hz, 2H), 2.90 (t, J= 6.4 Hz, 2H).
Example 12 2-(3,5-Dichloro-44(1-oxo-2-((tetrahydro-2H-pyran-4-yOmethyl)-1,2,3,4-16 tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 oH 0 H N1III z N
N m Step 1 Step 2 Step 3 - NO2 Step 4 5a 12a 12b 12c CI
CI CI

CI NH Step 5 '1,1IH 0 Step 6 Oa,rri j0 'IV 2 0 NHCOOEt 17 12d 12e CN 12 CN

Step 1: Synthesis of 6-methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12a [00255] 6-Methoxy-3,4-dihydroisoquinolin-1(211)-one 5a (3.0 g, 16.9 mmol) was dissolved in a mixture solution of THF (30 mL) and N,N-dimethylacetamide (15 mL). Sodium hydride (0.85 g, 21.2 mmol, 60% in oil) was added in portions at 0 C, then bromomethylpyran (1.13 mL, 13.8 mmol) was added dropwise. After the addition was complete, the reaction was continued at room temperature for 24 hours. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with saturated sodium chloride (40 mL x 3), dried over anhydrous sodium sulfate and concentrated by suction filtration.
The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give light CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yellow oil 12a (4.35 g, yield 93%).
2 MS (ESI, pos. ion) m/z: 276.2 [M+H]t 3 Step 2: Synthesis of 6-hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12b 4 [00256] 6-Methoxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12a (0.81 g, 2.94 mmol) was dissolved in dichloromethane (20 mL). Boron tribromide (0.57 mL, 5.89 mmol) was slowly added 6 dropwise at 0 C and the mixture was reacted at 0 C for 2.5 hours. The reaction was quenched by adding methanol 7 (5 mL) at 0 C. The mixture was concentrated, and water (50 mL) was added.
The mixture was extracted with ethyl 8 acetate (40 mL x 3). The combined organic layers were washed with saturated sodium chloride (40 mL x 2), dried 9 over anhydrous sodium sulfate and concentrated by suction filtration. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give a light yellow solid 126 (0.42 g, yield 11 55%).
12 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-13 dihydroisoquinolin-1(2H)-one 12c 14 [00257] To a solution of 6-hydroxy-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12b (0.33 g, 1.3 mmol) in N,N-dimethylformamide (10 mL) were added 1,2,3-trichloro-5-nitrobenzene (0.39 g, 16 1.7 mmol) and potassium carbonate (0.55 g, 3.9 mmol), and the mixture was reacted at 80 C for 5 hours. The 17 reaction solution was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with 18 ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated sodium chloride (15 mL x 3), 19 dried over anhydrous sodium sulfate and concentrated by suction filtration. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give a yellow solid 12c (0.31 g, yield 21 54%).
22 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-23 dihydroi soquinol in -1(2H)-one 12d 24 [00258] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-((tetrahydro-2H-pyran-4-yOmethyl)-3,4-dihydroisoquinolin-1(2H)-one 12c (0.31 g, 0.69 mmol) in acetic acid (10 mL) was added iron powder (0.19 g, 3.3 26 mmol), and the mixture was reacted at 60 C for 3.5 hours. The reaction solution was cooled to room temperature, 27 iron powder was removed, and water (10 mL) was added. The mixture was extracted with ethyl acetate (15 mL ><
28 3). The combined organic layers were washed with saturated sodium chloride (15 mL x 3), dried over anhydrous 29 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give a light yellow solid 12d (0.18 g, yield 62%).
31 MS (ESL, pos. ion) m/z: 421.1 [M+H]t 32 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-33 1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 12e 34 [00259] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one 12d (0.18 g, 0.43 mmol) in acetic acid (8 mL) was slowly added a solution of sodium CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 nitrite (46 mg, 0.65 mmol) in water (0.5 mL) dropwise at 0 C. The mixture was reacted for 20 minutes, then N-2 cyano-acetylurethane (75 mg, 0.47 mmol) was added, and the reaction was continued for 4.5 hours. Water (10 mL) 3 was added to the reaction solution. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic 4 layers were washed with saturated sodium chloride (15 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a yellow solid 12e (0.25 g, yield 99%).
6 MS (ESL, neg. ion) m/z: 586.1 [M-H].
7 Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-8 tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 9 [00260] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-41-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 12e (0.25 g, 0.43 mmol) in N,N-11 dimethylformamide (8 mL) was added sodium acetate (0.18 g, 2.2 mmol), and the mixture was reacted at 120 C for 12 4 hours. The reaction solution was cooled to room temperature, and water (15 mL) was added. The mixture was 13 extracted with ethyl acetate (15 mL >< 3). The combined organic layers were washed with saturated sodium chloride 14 solution (15 mL x 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1), and the obtained 16 solid was recrystallized (petroleum ether/ethyl acetate = 3/1, 5 mL) to obtain a white solid 12 (0.21 g, yield 89%, 17 HPLC purity: 97.04%).
18 MS (ESL, neg. ion) m/z: 540.1 [M-H].
19 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 7.88-7.80 (m, 3H), 6.85-6.78 (m, 211), 3.86-3.80 (m, 2H), 3.53 (t, J= 6.4 Hz, 2H), 3.35 (s, 2H), 3.25 (t, J= 11.2 Hz, 2H), 2.95 (t, J= 6.3 Hz, 2H), 1.95-1.85 (m, 1H), 21 1.53 (d, J= 11.6 Hz, 2H), 1.21 (ddd, J= 16.5, 12.4, 5.4 Hz, 2H).
22 Example 13 2-(3,5-Dichloro-4-((2-(isopropoxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-23 yl)oxylpheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 13 f cr NH
IT '5- CI' 'NH

ON
[00261] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-26 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) in isopropanol (10 mL) was added 37%
27 formaldehyde (1.5 mL, 20 mmol). The mixture was sealed and reacted at 100 C for 24 hours. The reaction solution 28 was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel column 29 chromatography (petroleum ether/ethyl acetate = 1/1), and the obtained solid was recrystallized (ethyl acetate/petroleum ether = 1/2, 6 mL) to obtain a white solid 13 (85 mg, yield 24%, HPLC purity: 99.85%).
31 MS (ESL, neg. ion) m/z: 514.1 [M-H];

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.97-7.79 (m, 3H), 6.87 (dd, J= 17.0, 4.9 Hz, 2H), 2 4.92 (s, 2H), 3.67 (dt, J= 12.2, 6.1 Hz, 1H), 3.56 (t, J= 6.5 Hz, 2H), 2.97 (t, J= 6.3 Hz, 2H), 1.10 (d, J= 6.1 Hz, 3 6H).
4 Example 14 2-(3,5-Dichloro-44(1-oxo-2-((2,2,2-trifluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 14 I CI
Hrisj o I Fo,,t1 I si:*N

Criq "Tc'N

7 [00262] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-8 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.48 g, 1.08 mmol) in trifluoroethanol (8 mL) was added 9 37% formaldehyde (1.60 mL, 22 mmol). The mixture was sealed and reacted at 100 C for 24 hours. The reaction solution was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel column 11 chromatography (petroleum ether/ethyl acetate = 1/2), and the obtained solid was recrystallized (ethyl 12 acetate/petroleum ether = 1/2, 6 mL) to obtain a white solid 14 (0.23 g, yield 38%, HPLC purity: 96.05%).
13 MS (ESL neg. ion) m/z: 554.0 [M-11]-;
14 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 111), 7.93 (d, J= 8.6 Hz, 1H), 7.90-7.79 (m, 2H), 6.93-6.83 (m, 2H), 5.07 (s, 2H), 4.12 (q, J= 9.4 Hz, 2H), 3.63 (t, J= 6.4 Hz, 2H), 3.01 (t, J= 6.4 Hz, 2H);
16 19F NMR (376 MHz, DMSO-d6) 8 (ppm) -73.04.
17 Example 15 2-(3,5-dichloro-441-oxo-242,2-difluoroethoxy)methyl)-1,2,3,4-tetrahydroisoquinolin-6-18 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 15 o GI
j I I o ni 1 01" '!;I. N11-1 F CI Nil NH
Ny0 0 N

CN
[00263] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-21 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.30 g, 0.68 mmol) in 2,2-difluoroethanol (6 mL) was 22 added 37% formaldehyde (1.0 mL, 14 mmol). The mixture was sealed and reacted at 100 C for 24 hours. The 23 reaction solution was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel 24 column chromatography (petroleum ether/ethyl acetate = 1/2), and the obtained solid was recrystallized (ethyl acetate/petroleum ether = 1/2, 6 mL) to obtain a white solid 15 (85 mg, yield 23%, HPLC purity: 97.53%).
26 MS (ESL neg. ion) m/z: 536.1 [M-11]-;

NMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 111), 7.89 (dd, J= 27.8, 8.3 Hz, 3H), 6.95-6.78 (m, 2H), 28 6.14 (t, J= 55.1 Hz, 1H), 5.01 (s, 2H), 3.74 (t, J= 14.8 Hz, 2H), 3.61 (s, 2H), 3.00 (s, 2H);

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 19F NMR (376 MHz, DMSO-d6) 8 (ppm) -125.56.
2 Example 16 2-(3,5-dichloro-4-((2-(1-ethoxyethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-y1)oxy)phenyl)-3 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 16 HNI I
---ff- NH NH

CN
[00264] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-6 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) in ethanol (4 mL) was added 7 acetaldehyde (0.8 mL, 14 mmol). The mixture was sealed and reacted at 90 C for 48 hours. The reaction solution 8 was cooled to room temperature, and concentrated. The resulting residue was purified by silica gel column 9 chromatography (petroleum ether/ethyl acetate = 1/2), and the obtained solid was recrystallized (ethanol/ethyl acetate/petroleum ether = 1/7/10, 18 mL) to obtain a yellow solid 16 (60 mg, yield 26%, HPLC purity: 87.08%).
11 MS (ESL neg. ion) m/z: 514.1 [M-H];
12 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.90 (d, J= 8.6 Hz, 1H), 7.85 (s, 211), 6.93-6.78 (m, 13 2H), 5.89 (q, J= 6.0 Hz, 1H), 3.41 (s, 2H), 3.39 (d, J= 7.0 Hz, 2H), 2.95 (t, J= 6.5 Hz, 2H), 1.26 (d, J= 6.1 Hz, 14 3H), 1.11 (t, J= 7.0 Hz, 3H).
Example 17 2-(3,5-Dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-16 3,5(2H,41/)-dione 17 CI CI CI
,o1), 0 ,o..x) 0 Fli; H.HNrC
CI' NI" NH CI' N" NH ______ --PL'N NH
Step 1 I
0 0 N Step 2 17 CN 17a COOH 17 18 Step 1: Synthesis of 2-(3,5-dichloro-4-((l-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-19 2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 17a [00265] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-21 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) in acetic acid (4 mL) was added 22 concentrated hydrochloric acid (1.5 mL). The mixture was reacted at 120 C for 16 hours. The reaction solution was 23 cooled to room temperature, then water (6 mL) was added. The reaction mixture was stirred for 5 minutes, then 24 filtered, and the filter cake was collected and dried to obtain a yellow solid 17a (90 mg, yield 87%).
MS (ESL neg. ion) m/z: 463.0 [M-H].
26 Step 2: Synthesis of 2-(3,5-dichloro-4-((1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-27 3,5(2H,411)-dione 17 28 [00266] 2-(3,5-Dichloro-4-((1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 tetrahydro-1,2,4-triazine-6-carboxylic acid 17a (175 mg, 0.38 mmol) was dissolved in thioglycolic acid (2.5 mL).
2 The mixture was reacted at 140 C for 17 hours. The reaction solution was cooled to room temperature, and water 3 (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 2). The combined 4 organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The obtained residue was purified by silica gel column chromatography (100%
6 ethyl acetate) to give a light red solid 17 (63 mg, yield 40%, HPLC
purity: 95.58%).
7 MS (ESL, neg. ion) m/z: 418.0[M-H]-;
8 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.52 (s, 1H), 7.85 (d, J= 10.5 Hz, 411), 7.73 (s, 111), 6.85 (d, J= 2.6 9 Hz, 1H), 6.78 (dd, J= 8.6, 2.6 Hz, 1H), 3.57- 3.38 (m, 2H), 2.89 (t, J=
6.6 Hz, 2H).
Example 18 2-(4-((2-Benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)-3,5-dichloropheny1)-3,5-11 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 so HN OH ,C
Step 1 Step 2: Step 3 41111 N
'-'"? CI NO Step 4 5a 18a 18b 18c CI CI
0 CI 0.
nLr); 0 k r N 'NH 0 ,N1r "2 Step 5 Step 6 CI
N NH

yll-NHCOOEt 0 12 18d 18e CN 18 ON
13 Step 1: Synthesis of 2-benzy1-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 18a 14 [00267] At 0 C, to a mixed solution of sodium hydride (0.81 g, 20 mmol, 60% in oil) in N,N-dimethylformamide (24 mL) and tetrahydrofuran (18 mL) was added 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 16 5a (3.0 g, 17 mmol). Benzyl bromide (2.2 mL, 19 mmol) was added dropwise. The mixture was reacted at room 17 temperature for 6 hours. The reaction was quenched by adding water (120 mL). The mixture was extracted with 18 ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated sodium chloride (50 mL x 2), 19 dried over anhydrous sodium sulfate, and concentrated by suction filtration to give light yellow oil 18a (4.51 g, 100% yield).
21 Step 2: Synthesis of 2-benzy1-6-hydroxy-3,4-dihydroisoquinolin-1(21/1-one 18b 22 [00268] At 0 C, to a solution of 2-benzy1-6-methoxy-3,4-dihydroisoquinolin-1(211)-one 18a (4.5 g, 17 mmol) 23 in dichloromethane (36 mL) was added boron tribromide (3.2 mL, 34 mmol) dropwise. Then the mixture was reacted 24 at room temperature for 5 hours. The reaction solution was quenched by pouring into ice water (100 mL). The mixture was stirred for 10 minutes, then filtered, and the filter cake was washed with water (20 mL x 2), and the 26 filter cake was collected and dried to obtain a white solid 18b (3.8 g, yield 89%).
27 Step 3: Synthesis of 2-benzy1-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 18c 28 [00269] To a solution of 2-benzy1-6-hydroxy-3,4-dihydroisoquinolin-1(211)-one 18b (3.80 g, 15.0 mmol) and 29 1,2,3-trichloro-5-nitrobenzene (3.74 g, 16.5 mmol) in NN-dimethylfomnamide (23 mL) was added potassium CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 carbonate (3.14 g, 22.5 mmol), and the mixture was reacted at 70 C for 7 hours. The reaction solution was cooled 2 to room temperature, then water (50 mL) was added. The reaction mixture was stirred for 10 minutes and filtered.
3 The filter cake was washed with water (20 mL x 2). The collected filter cake was recrystallized (ethyl 4 acetate/petroleum ether = 1/2, 30 mL) to obtain an off-white solid 18c (6.10 g, yield 92%).
Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-benzy1-3,4-dihydroisoquinolin-1(211)-one 18d 6 [00270] To a solution of 2-benzy1-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(211)-one 18c 7 (3.0 g, 6.8 mmol) in acetic acid (18 mL) was added iron powder (1.1 g, 20 mmol), and the mixture was reacted at 8 60 C for 3 hours. The reaction solution was cooled to room temperature, then water (40 mL) was added. The reaction 9 mixture was stirred for 10 minutes and filtered. The filter cake was washed with water (20 mL x 2). The collected filter cake was recrystallized (ethyl acetate/petroleum ether = 2/1, 15 mL) to obtain a brown solid 18d (1.1 g, yield 11 39%).
12 Step 5: Synthesis of ethyl (2-(2-(44(2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-13 di chloroph enyl)hydrazono)-2-cyanoacetypearbamate 18e 14 [00271] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-benzy1-3,4-dihydroisoquinolin-1(2H)-one 18d (1.0 g, 2.4 mmol) and N-(2-cyanoacetyl) carbamate (0.45 g, 2.9 mmol) in acetic acid (20 mL) was added a solution 16 of sodium nitrite (0.33 g, 4.8 mmol) in water (10 mL), and the mixture was continued to react at 0 C for 2 hours.
17 At 0 C, water (30 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, then filtered, and 18 the filter cake was washed with water (10 mL). Then the filter cake was collected and dried to obtain a yellow solid 19 18e (0.60 g, yield 43%).
Step 6: Synthesis of 2-(44(2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)-3,5-dichloropheny1)-3,5-21 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 22 [00272] To a solution of ethyl (2-(2-(4-((2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)-3,5-23 dichlorophenyl)hydrazono)-2-cyanoacetyl)carbamate 18e (0.70 g, 1.2 mmol) in N,N-dimethylformamide (7 mL) 24 was added sodium acetate (0.11 g, 1.3 mmol), and the mixture was reacted at 120 C for 4 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl 26 acetate/petroleum ether (2/1, 30 mL x 3). The combined organic layers were washed with saturated sodium chloride 27 solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was 28 recrystallized (ethanol/ethyl acetate/petroleum ether-1/3/6, 50 mL) to obtain a red solid 18 (0.26 g, yield 40%, 29 HPLC purity: 98.24%).
MS (ESL, neg. ion) m/z: 533.4[M-11]-;
31 11-1 NMR (400 MHz, DMSO-d6)13 (ppm) 7.94 (d, J= 8.6 Hz, 1H), 7.84 (s, 2H), 7.32(dq, J= 19.3, 11.0, 9.3 Hz, 32 5H), 6.85 (d, J = 6.9 Hz, 2H), 4.70 (s, 211), 3.47(s, 3H), 2.95 (s, 2H).
33 Example 19 2-(3,5-Dichloro-4-01-oxo-1,2-dihydroisoquinolin-6-ylloxylpheny1)-3,5-dioxo-2,3,4,5-34 tetrahydro-1,2,4-triazine-6-carbonitrile 19 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 o I
OH
20,õ
HN I HN
b,IH 0 Step 1 HN .
CI NO2 Step 2 HN ci .--- NH2 Step 3 NHCOOEt 19ao 19b 190 19d CN
CI
0, r, Step 4 -11-' 2 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)isoquinolin-1(2H)-one 19b 3 [00273] To a solution of 6-hydroxyisoquinolin-1(2H)-one 19a (0.92 g, 5.7 mmol) in N, N-dimethylformamide 4 (20 mL) were added 1,2,3-trichloro-5-nitrobenzene (1.40 g, 6.18 mmol) and potassium carbonate (1.90 g, 13.6 mmol), and the mixture was reacted at 80 C for 3 hours. The reaction solution was cooled to room temperature, and 6 water (50 mL) was added. The mixture was extracted with ethyl acetate (35 mL x 3). The combined organic layers 7 were washed with saturated sodium chloride (35 mL x 3), dried over anhydrous sodium sulfate and concentrated by 8 suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =
9 2/1) to give a yellow solid 196 (1.83 g, yield 91%).
MS (ESL pos. ion) m/z: 351.1 [M+H]t 11 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)isoquinolin-1(2H)-one 19c 12 [00274] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)isoquinolin-1(2H)-one 19b (0.45 g, 1.30 mmol) in 13 acetic acid (15 mL) was added iron powder (0.29 g, 5.1 mmol), and the mixture was reacted at 60 C for 2.5 hours.
14 The reaction solution was cooled to room temperature, iron powder was removed, then water (30 mL) was added.
The reaction mixture was stirred for 10 minutes, and filtered. The filter cake was collected and dried to obtain a 16 light yellow solid 19c (0.38 g, yield 92%).
17 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-1,2-dihydroisoquinolin-6-18 yl)oxy)phenyphydrazono)acetyl)carbamate 19d 19 [00275] To a solution of 6-(4-amino-2,6-dichlorophenoxy)isoquinolin-1(2H)-one 19c (0.40 g, 1.20 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (0.13 g, 1.8 mmol) in water (1.5 mL) dropwise at 0 C.
21 The mixture was reacted for 20 minutes, then N-cyanoacetylurethane (0.22 g, 1.40 mmol) was added, and the
22 reaction was continued for 4 hours. Water (30 mL) was added to the reaction solution. The mixture was extracted
23 with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated sodium chloride (35 mL
24 x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a yellow solid 19d (0.60 g, yield 99%).
26 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-1,2-dihydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-27 tetrahydro-1,2,4-triazine-6-carbonitrile 19 28 [00276] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((l-oxo-1,2-dihydroisoquinolin-6-29 yl)oxy)phenyphydrazono)acetyl)carbamate 19d (0.45 g, 0.92 mmol) in N,N-dimethylformamide (15 mL) was added CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 sodium acetate (0.38 g, 4.61 mmol), and the mixture was reacted at 120 C
for 3 hours. The reaction solution was 2 cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL ><
3 3). The combined organic layers were washed with saturated sodium chloride (30 mL x 3), dried over anhydrous 4 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give a white solid 19 (0.23 g, yield 55%, HPLC purity: 96.04%).
6 MS (ESL, neg. ion) m/z: 440 [M-H]-;
7 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.32 (s, 1H), 11.20 (d, J= 3.8 Hz, 1H), 8.21 (d, J= 8.8 Hz, 1H), 8 7.86 (s, 2H), 7.24-7.10 (m, 2H), 7.02 (s, 1H), 6.52 (d, J= 7.1 Hz, 1H).
9 Example 20 2-(3,5-dichloro-4-02-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 20 r -yo õi!( NO2 F. r, y õICki HN.T.1,3 Step 1 4,TrUcik-).- No, Step 2 20b CINH2 Step 3 CI

lb 20a CI CI
CI
0, NH 0 Step 4 G tel N NH
S p FiçyCI /II NH

N NHCOOEt 0 0 N<)0 20c CN 20d CN
20e COOH
CI
Step b NY CI' -N NH
"113 12 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 13 20a 14 [00277] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(21-1)-one lb (0.50 g, 1.4 mmol) in THF (20 mL) was added sodium hydride (85 mg, 2.1 mmol, 60 mass% in oil) at 0 C. After 20 minutes of 16 reaction, 1-bromomethy1-4-fluorobenzene (0.55 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added 17 dropwise, and the mixture was reacted at room temperature for 15 hours.
The reaction was quenched with ice water 18 (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with 19 saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give light yellow 21 oil 20a (0.65 g, yield 99%).
22 MS (ESL, pos. ion) m/z: 461.2[M+H];
23 'H NMR (400 MHz, CDC13) 8 (ppm) 8.35 (s, 2H), 8.14 (d, J= 8.6 Hz, 1H), 7.37-7.30 (m, 2H), 7.07-7.00 (m, 24 2H), 6.79 (dd, J= 8.7, 2.6 Hz, 1H), 6.64 (d, J= 2.5 Hz, 1H), 4.76 (s, 2H), 3.51 (t, J= 6.6 Hz, 2H), 2.93 (t, J= 6.6 Hz, 2H).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 2: Synthesis of 644-amino-2,6-dichlorophenoxy)-244-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 2 20b 3 [00278] To a solution of 642,6-dichloro-4-nitrophenoxy)-244-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-4 one 20a (0.65 g, 1.4 mmol) in acetic acid (10 mL) was added iron powder (0.16 g, 2.8 mmol), and the mixture was reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature. The reaction was quenched 6 with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were 7 washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction 8 filtration. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =
9 1/1) to give light yellow oil 20b (0.37 g, yield 61%).
MS (ESL, pos. ion) m/z: 431.0 [M+H]t 11 Step 3: Synthesis of ethyl (2-cyano-242-(3,5-dichloro-44(244-fluorobenzyl)-1-oxo-1,2,3,4-12 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 20c 13 [00279] To a solution of 644-amino-2,6-dichlorophenoxy)-244-fluorobenzy1)-3,4-dihydroisoquinolin-14 1(211)-one 20b (0.37 g, 0.86 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (0.12 g, 1.7 mmol) in water (6 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.20 g, 1.3 mmol) was added. The mixture was 16 reacted for 3 hours. Water (30 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, then 17 filtered, and the filter cake was washed with water (5 mL). Then the filter cake was collected and dried to obtain a 18 light yellow solid 20c (0.50 g, yield 97%).
19 MS (ESL, pos. ion) m/z: 596.0 [M+H]t Step 4: Synthesis of 243,5-dichloro-44(244-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-21 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 20d 22 [00280] To a solution of ethyl (2-cyano-2-(243,5-dichloro-4#2-(4-fluorobenzy1)-1-oxo-1,2,3,4-23 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 20c (0.50 g, 0.84 mmol) in N,N-24 dimethylformamide (10 mL) was added sodium acetate (0.15 g, 1.1 mmol), and the mixture was reacted at 120 C
for 6 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 26 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, 27 recrystallized (ethyl acetate/petroleum ether = 2/1, 15 mL) at 60 C to obtain a yellow solid 20d (0.28 g, yield 61%, 28 HPLC purity: 100%).
29 MS (ESL, neg. ion) m/z: 550.0 [M-1-1]-;
'H NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.94 (dd, J = 9.0, 6.2 Hz, 1H), 7.84 (s, 2H), 7.36 (dd, 31 J= 8.4, 5.5 Hz, 2H), 7.16 (t, J= 8.7 Hz, 2H), 6.85 (d, J= 6.7 Hz, 2H), 4.67 (s, 2H), 3.47 (t, J= 6.6 Hz, 211), 2.95 32 (t, J= 6.6 Hz, 2H);
33 19F NMR (376 MHz, DMSO-d6) 8 (,pm) -115.68.
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 5: Synthesis of 2-(3,5-dichloro-44(2-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-2 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 20e 3 [00281] 2-(3,5-Dichloro-442-(4-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-4 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 20d (0.17 g, 0.31 mmol) was dissolved in acetic acid (4 mL), then concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 C for 18 hours. The reaction 6 solution was cooled to room temperature, then water (18 mL) was added.
The reaction mixture was stirred for 10 7 minutes, filtered, and rinsed with water (10 mL X 2). The filter cake was collected and dried to obtain a yellow solid 8 20e (0.15 g, yield 85%).
9 Step 6: Synthesis of 2-(3,5-dichloro-4-42-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,411)-dione 20 11 [00282] 2-(3,5-Dichloro-442-(4-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-12 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 20e (0.15 g, 0.26 mmol) was dissolved in thioglycolic acid 13 (3 mL). The mixture was reacted at 150 C for 24 hours. The reaction solution was cooled to room temperature, and 14 ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate 16 and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography 17 (petroleum ether/ethyl acetate = 1/1) to give a white solid 20 (90 mg, yield 65%, HPLC purity: 98.12%).
18 MS (ESL neg. ion) m/z: 525.0 [M-H];
19 11-1 NMR (400 MHz, DMSO-d6) 13 (ppm) 12.52 (s, 1H), 7.93 (d, J= 8.6 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.36 (dd, J= 8.5, 5.6 Hz, 2H), 7.16 (dd, J= 10.1, 7.6 Hz, 2H), 6.83 (s, 1H), 6.81 (d, J= 2.6 Hz, 1H), 4.67 (s, 2H), 21 3.47 (t, J= 6.6 Hz, 211), 2.95 (t, J= 6.6 Hz, 211).
22 Example 21 2-(3,5-dichloro-4-42-(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-23 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 21 ci r,-HN CINO2 Step 1 4111 1'1 I =NO. Step 2 1.1 11;1 CINH, Step 3 C
0 lb 021a 21b CI CI
CI
N 0,r1,5 0 40 lt __ , 40 11 C1 N ----NH 0 Step 4 N"
'NH step 5 41 N CI N- NH
0 NHCOOEt 0 -L0 21c CN 21d CN
21e COOH
CI
di 0 Step 6 1eJLCI NNH

Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-methylbenzy1)-3,4-dihydroisoquinolin-1(2H)-one CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 21a 2 [00283] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(21-1)-one lb (0.50 g, 1.4 3 mmol) in THF (20 mL) was added sodium hydride (85 mg, 2.1 mmol, 60 mass%
in oil). After 20 minutes of reaction, 4 1-bromomethy1-4-toluene (0.54 g, 2.8 mmol) and N,N-dimethylformamide (5 mL) were added dropwise, and the mixture was reacted at room temperature for 14 hours. The reaction was quenched with ice water (30 mL). The 6 mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated 7 sodium chloride (30 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue 8 was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give light yellow oil 21a 9 (0.63 g, yield 98%).
Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzy1)-3,4-dihydroisoquinolin-1(21-1)-one 11 21b 12 [00284] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-methylbenzy1)-3,4-dihydroisoquinolin-13 1(21-1)-one 21a (0.63 g, 1.4 mmol) in acetic acid (10 mL) was added iron powder (0.16 g, 2.8 mmol), and the mixture 14 was reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2).
The combined organic layers were 16 washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction 17 filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to 18 give light yellow oil 216 (0.46 g, yield 78%).
19 MS (ESL, pos. ion) m/z: 428.1 [M+H]+.
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(4-methylbenzy1)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 21c 22 [00285] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-methylbenzy1)-3,4-dihydroisoquinolin-23 1(21-1)-one 21b (0.46 g, 1.1 mmol) in acetic acid (16 mL) was added a solution of sodium nitrite (0.15 g, 2.1 mmol) 24 in water (8 mL) at 0 C, then N-cyanoacetylurethane (0.25 g, 1.6 mmol) was added. The mixture was reacted for 2.5 hours. Water (30 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, filtered, and the 26 filter cake was washed with water (5 mL). Then the filter cake was collected and dried to obtain a light yellow solid 27 21c (0.48 g, yield 75%).
28 MS (ESL pos. ion) m/z: 595.0 [M+H]t 29 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5 -dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 21d 31 [00286] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-42-(4-methylbenzy1)-1-oxo-1,2,3,4-32 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 21c (0.48 g, 0.81 mmol) in N,N-33 dimethylformamide (10 mL) was added sodium acetate (0.14 g, 1.0 mmol), and the mixture was reacted at 120 C
34 for 8 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and dried, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 recrystallized (ethyl acetate/petroleum ether = 2/1, 15 mL) at 60 C to obtain a yellow solid 21d (0.41 g, yield 93%, 2 11PLC purity: 98.71%).
3 MS (ESL neg. ion) m/z: 547.0 [M-11]-;
4 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.33 (s, 1H), 7.97-7.89 (m, 1H), 7.84 (s, 2H), 7.20 (d, J= 7.7 Hz, 2H), 7.14 (d, J= 7.8 Hz, 2H), 6.85 (dd, J= 5.8, 2.9 Hz, 2H), 4.64 (s, 2H), 3.44 (t, J= 6.5 Hz, 2H), 2.93 (t, J= 6.6 6 Hz, 2H), 2.28 (s, 3H).
7 Step 5: Synthesis of 2-(3,5-dichloro-4-42-(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-8 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 21e 9 [00287] 243,5 -Dichloro-442 -(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 21d (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), 11 then concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 C for 18 hours. The reaction 12 solution was cooled to room temperature, then water (18 mL) was added.
The reaction mixture was stirred for 10 13 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 14 21e (0.20 g, yield 93%).
Step 6: Synthesis of 2-(3,5-dichloro-44(2-(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-16 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 21 17 [00288] 2-(3,5-Dichloro-44(2-(4-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroi soquinol in -6-yl)oxy)ph eny1)-3,5-18 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 21e (0.20 g, 0.35 mmol) was dissolved in thioglycolic acid 19 (3 mL). The mixture was reacted at 150 C for 24 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium 21 bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate 22 and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography 23 (petroleum ether/ethyl acetate = 1/1) to give a yellow solid 21 (96 mg, yield 52%, HPLC purity: 96.18%).
24 MS (ESL neg. ion) m/z: 521.0 [M-11]-;
111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.53 (s, 1H), 7.93 (d, J= 9.2 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 26 7.23-7.11 (m, 411), 6.82 (s, 1H), 6.80 (d, J= 2.6 Hz, 11-1), 4.64 (s, 211), 3.44 (d, J= 6.5 Hz, 2H), 2.92 (t, J= 6.6 Hz, 27 2H), 2.27 (s, 3H).
28 Example 22 2-(4-((2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)-3,5-dichloropheny1)-1,2,4-29 triazine-3,5(2H,41/)-dione 22 NH Step 1 ,a), 0 0 CI
NH step 2 141111 18 CN 22a COOH 22 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 1: Synthesis of 2-(44(2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)-3,5-dichloropheny1)-3,5-2 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 22a 3 [00289] 2-(442-8 enzyl-l-oxo-1,2,3,4 -tetrahydroisoquinolin-6-ypoxy)-3,5 -dichloropheny1)-3,5-dioxo-4 2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 18 (0.21 g, 0.37 mmol) was dissolved in acetic acid (4 mL), then concentrated hydrochloric acid (1.5 mL) was added. The mixture was reacted at 120 C for 24 hours. The reaction 6 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 7 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 8 22a (0.20 g, yield 100%).
9 Step 2: Synthesis of 2-(4-((2-benzy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)-3,5-dichloropheny1)-1,2,4-triazine-3,5(2H,41-1)-dione 22 11 [00290] 2-(442-B enzyl-l-oxo-1,2,3,4 -tetrahydroisoquinolin-6-ypoxy)-3,5 -dichloropheny1)-3,5-dioxo-12 2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 22a (0.20 g, 0.36 mmol) was dissolved in thioglycolic acid (4 13 mL). The mixture was reacted at 160 C for 24 hours. The reaction solution was cooled to room temperature, and 14 water (10 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by 16 suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =
17 1/1) to give a light yellow solid 22 (0.13 g, yield 68%, HPLC purity:
98.02%).
18 MS (ESL, neg. ion) m/z: 507.5 [M-H];
19 111 NMR (400 MHz, DMSO-d6) 13 (ppm) 12.51 (s, 1H), 7.92 (d, J= 8.7 Hz, 1H), 7.85 (s, 2H), 7.72 (s, 1H), 7.35- 7.22 (m, 5H), 6.81 (d, J= 7.6 Hz, 2H), 4.68 (s, 2H), 3.45 (t, J= 6.4 Hz, 2H), 2.93 (t, J= 6.2 Hz, 2H).
21 Example 23 2-(3,5-dichloro-441-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-22 tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione a a a ,N1 o0 ft ______ oa, w CIN- NH Step 1a 0 '.- CI N -NH st,p 2 N.... CI 4.11.-. N
NH
23 12 CN 23a COOH 23 24 Step 1: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 23a 26 [00291] 2-(3,5-Dichloro-4-((1 -oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-27 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 12 (1.3 g, 2.4 mmol) was dissolved in 28 acetic acid (20 mL), then concentrated hydrochloric acid (6 mL) was added. The mixture was reacted at 120 C for 29 4.5 hours. The reaction solution was cooled to room temperature, and concentrated. Then water (25 mL), saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, and 31 extracted with water (25 mL x 2). The aqueous layer was collected, and adjusted the pH value to 2-3 with dilute 32 hydrochloric acid (4 N), then extracted with ethyl acetate (25 mL x 3).
The extracted organic layers after CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 acidification were combined, washed with saturated sodium chloride (25 mL
X 3), dried over anhydrous sodium 2 sulfate, and concentrated by suction filtration to give a yellow solid 23a (0.87 g, yield 65%).
3 Step 2: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-4 tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 23 [00292] 2-(3,5-Dichloro-4-((1 -oxo-2-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-6 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 23a (0.85 g, 1.5 mmol) was dissolved 7 in thioglycolic acid (4 mL). The mixture was reacted at 160 C for 24 hours. The reaction solution was cooled to 8 room temperature, and saturated sodium bicarbonate solution (15 mL) was slowly added. The mixture was extracted 9 with ethyl acetate (15 mL X 3). The combined organic layers were washed with saturated sodium chloride (15 mL
X 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica 11 gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give a light yellow solid 23 (0.42 g, yield 54%, 12 HPLC purity: 96.10%).
13 MS (ESI, neg. ion) m/z: 515.2 [M-1-1]-;
14 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.51 (s, 1H), 7.94-7.82 (m, 3H), 7.72 (s, 1H), 6.87-6.75 (m, 2H), 3.83 (d, J= 8.9 Hz, 211), 3.53 (t, J= 6.4 Hz, 2H), 3.35 (s, 211), 3.25 (t, J=
11.1 Hz, 211), 2.94 (t, J= 6.2 Hz, 2H), 16 1.96-1.85 (m, 1H), 1.53 (d, J= 11.9 Hz, 2H), 1.24 (dd, J= 11.7, 4.0 Hz, 2H).
17 Example 24 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-18 yl)oxy)pheny1)l,2,4-triazine-3,5(2H,411)-dione 24 0 ci HN Step 1 NjL.N=
Na Step 2 N
Step 3 0 lb 024a 24b CI

40 N 0 so Na CI NH 0 Step 4 CI N NH
Step 5 CI N NH

11 rLID N)INHCOOEt 246 CN 24d CN
24e COOH
CI
0, N
Step CI0.., al" 'NH

Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-21 one 24a 22 [00293] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (2.0 g, 5.7 23 mmol) in THF (20 mL) was added sodium hydride (0.80 g, 20 mmol, 60 mass%
in oil) at 0 C. After 20 minutes of 24 reaction, 4-(bromomethyl)pyridine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (3 mL) were added, and the mixture was reacted at 5 C for 2 hours. Water (70 mL) was added to quench the reaction. The mixture 26 was stirred for 10 minutes, filtered, and the filter cake was washed with water (20 mL X 3). Then the filter cake was CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 collected and dried to obtain a yellow solid 24a (2.3 g, yield 91%).
2 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(211)-3 one 24b 4 [00294] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-1(21/)-one 24a (1.9 g, 4.3 mmol) in acetic acid (25 mL) was added iron powder (0.60 g, 11 mmol), and the mixture 6 was reacted at 55 C for 8 hours. The reaction solution was cooled to room temperature, then water (120 mL) was 7 added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic 8 layers were washed with saturated sodium chloride (30 mL x 2), dried over anhydrous sodium sulfate, and 9 concentrated by suction filtration to give a gray solid 24b (1.8 g, yield 100%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-11 tetrahydroisoquinolin-6-ypoxy)phenyfihydrazono)acetyl)carbamate 24c 12 [00295] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-ylmethyl)-3,4-dihydroisoquinolin-13 1(211)-one 24b (1.8 g, 4.3 mmol) in acetic acid (27 mL) was added a solution of sodium nitrite (0.60 g, 8.7 mmol) 14 in water (14 mL) at 0 C, then N-cyanoacetylurethane (0.81 g, 5.3 mmol) was added. The mixture was reacted for 2 hours. Water (80 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 16 2). The combined organic layers were washed with saturated sodium chloride (50 mL x 3), dried over anhydrous 17 sodium sulfate, and concentrated by suction filtration to give a red foamy solid 24c (2.5 g, yield 99%).
18 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-19 ypoxy)pheny1)-3,5-dioxo-23,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 24d [00296] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yDoxy)phenyfihydrazono)acetypcarbamate 24c (1.8 g, 3.1 mmol) in N,N-22 dimethylformamide (20 mL) was added sodium acetate (0.28 g, 3.4 mmol), and the mixture was reacted at 120 C
23 for 6 hours. The reaction solution was cooled to room temperature, then water (100 mL) was added to quench the 24 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, recrystallized (N,N-dimethylformamide/ethanol/ethyl acetate/petroleum ether =
4/25/15/20, 128 mL) at 85 C to 26 obtain a yellow solid 24d (0.90 g, yield 53%, HPLC purity: 82.28%).
27 MS (ESL, pos. ion) m/z: 536.3 [M+H];
28 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 8.56 (s, 2H), 7.92 (d, J= 8.4 Hz, 1H), 7.84 (s, 2H), 7.33 (s, 2H), 6.86 29 (d, J= 13.0 Hz, 2H), 4.71 (s, 2H), 3.54 (s, 2H), 3.01 (s, 2H).
Step 5: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-31 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 24e 32 [00297] 243,5 -Dichloro-442 -(pyridin-4 -ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-33 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 24d (0.45 g, 0.84 mmol) was dissolved in acetic acid (8 34 mL), then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 24 hours. The CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred 2 for 10 minutes, filtered, and rinsed with water (10 mL X 2). The filter cake was collected and dried to obtain a light 3 yellow solid 24e (0.45 g, yield 97%).
4 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-4-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 24 6 [00298] 2-(3,5-Dichloro-4((2-(pyridin-4-ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-7 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 24e (0.37 g, 0.67 mmol) was dissolved in thioglyeolic 8 acid (5 mL). The mixture was reacted at 120 C for 36 hours. The reaction solution was cooled to room temperature, 9 and ethyl acetate (80 mL) was added. The mixture was washed successively with water (40 mL), saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL), then dried over anhydrous sodium 11 sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 12 (petroleum ether/ethyl acetate = 1/2) to give a light yellow solid 24 (0.20 g, yield 59%, HPLC purity: 92.08%).
13 MS (ESI, neg. ion) m/z: 511.3 [M+H];
14 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.53 (s, 1H), 8.77 (s, 2H), 7.92 (d, J= 8.5 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 111), 7.65 (s, 211), 6.87 (s, 1H), 6.83 (d, J= 7.6 Hz, 1H), 4.82 (s, 211), 3.59 (d, J= 6.2 Hz, 211), 3.03 (d, J=
16 6.5 Hz, 2H).
17 Example 25 2-(3,5-dichloro-4-((1-oxo-2-(pyridazin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-18 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 25 0 ci o,r?
HN
Step _________________________ 1 N = N
'N CI NO2 Step 2 N.LN
Step ________________________________________________________________________ 0 lb 026a 26b CI

N =
CI NH 0 Step 4 'N CI __ WILNH
Step 5 N

CI N KNH

NHCOOEt 0 N
-o 0 "IrLo 26c CN 26d CN
26e COOH
CI
Step 6 l'I'!()1 11 N" 'NH

20 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-21 1(211)-one 25a 22 [00299] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (2.0 g, 5.7 23 mmol) in THF (25 mL) was added sodium hydride (0.80 g, 20 mmol, 60 mass%
in oil). After 20 minutes of reaction, 24 3-(bromomethyl)pyridazine hydrobromide (1.5 g, 8.7 mmol) and N,N-dimethylformamide (4 mL) were added, and
25 the mixture was reacted at 8 C for 2 hours. Water (150 mL) was added to quench the reaction. The mixture was
26 stirred for 10 minutes, and filtered. The filter cake was rinsed with water (20 mL X 3), and the collected filter cake CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 was dried and slurried with ethyl acetate/petroleum ether (1/4, 50 mL).
The mixture was filtered, and the filter cake 2 was collected to obtain a yellow solid 25a (1.8 g, yield 71%).
3 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-4 1(211)-one 25b [00300] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-dihydroisoquinolin-6 1(211)-one 25a (1.0 g, 2.2 mmol) in acetic acid (15 mL) was added iron powder (0.35 g, 6.3 mmol), and the mixture 7 was reacted at 60 C for 8 hours. The reaction solution was cooled to room temperature, then water (80 mL) was 8 added to quench the reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (20 9 mL x 2). The filter cake was collected and dried to obtain a gray solid 25b (0.74 g, yield 79%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-11 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 25c 12 [00301] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridazin-3-ylmethyl)-3,4-13 dihydroisoquinolin-1(2M-one 25b (0.74 g, 1.8 mmol) in acetic acid (15 mL) was added a solution of sodium nitrite 14 (0.25 g, 3.6 mmol) in water (6 mL) at 0 C, then N-cyanoacetylurethane (0.35 g, 2.2 mmol) was added. The mixture was reacted for 2 hours. Water (50 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, 16 filtered, and the filter cake was washed with water (30 mL x 2). Then the filter cake was collected and dried to 17 obtain a red solid 25c (0.96 g, yield 93%).
18 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-19 yl)oxy)pheny1)-3,5 -dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 25d [00302] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 25c (0.96 g, 1.6 mmol) in N,N-22 dimethylformamide (12 mL) was added sodium acetate (0.15 g, 1.8 mmol), and the mixture was reacted at 120 C
23 for 6 hours. The reaction solution was cooled to room temperature, then water (100 mL) was added to quench the 24 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, recrystallized (N,N-dimethylformamide/ethanol/ethyl acetate/petroleum ether =
2/5/20/40, 128 mL) at 85 C to 26 obtain a yellow solid 24d (0.51 g, yield 58%, HPLC purity: 93.11%).
27 MS (ESL, pos. ion) m/z: 537.3 [M+H];
28 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.23 (s, 1H), 9.15 (d, J= 4.6 Hz, 1H), 7.88 (d, J= 28.0 Hz, 3H),
29 7.66 (dd, J= 10.8, 6.2 Hz, 2H), 7.06-6.64 (m, 2H), 4.97 (s, 2H), 3.66 (t, J= 6.6 Hz, 2H), 3.02 (t, J= 6.5 Hz, 2H).
Step 5: Synthesis of 2-(3,5-dichloro-44(2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-31 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 25e 32 [00303] 243,5 -Dichloro-442 -(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-33 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 25d (0.23 g, 0.43 mmol) was dissolved in 34 acetic acid (2.5 mL), then concentrated hydrochloric acid (1.4 mL) was added. The mixture was reacted at 120 C

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 for 24 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction 2 mixture was stirred for 10 minutes, filtered, and rinsed with water (15 mL X 2). The filter cake was collected and 3 dried to obtain a yellow solid 25e (0.21 g, yield 88%).
4 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 25 6 [00304] 2-(3,5-Dichloro-442-(pyridazin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 25e (0.20 g, 0.40 mmol) was 8 dissolved in thioglycolic acid (2.5 mL). The mixture was reacted at 120 C
for 36 hours. The reaction solution was 9 cooled to room temperature, and ethyl acetate (100 mL) was added. The mixture was washed successively with water (20 mL), saturated sodium bicarbonate solution (20 mL) and saturated sodium chloride solution (20 mL), then 11 dried over anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue was separated and 12 purified by pre-HPLC [35%ACN/65%H20 (1%TFA), Kromasil specifications:
C18 10p,mx50mmx250mm, flow 13 rate: 100 mL/min] to obtain a white solid 25 (20 mg, yield 20%, HPLC
purity: 82.95%).
14 MS (ESL neg. ion) m/z: 513.3 [M+Hr;
'H NMR (400 MHz, DMSO-d6) 13 (ppm) 12.52 (s, 1H), 9.17 (s, 1H), 7.99-7.83 (m, 3H), 7.79-7.51 (m, 3H), 16 6.96-6.74 (m, 2H), 4.95 (d, J= 17.0 Hz, 211), 3.67 (s, 2H), 3.02 (t, J=
6.5 Hz, 2H).
17 Example 26 2-(3,5-dimethy1-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxylpheny1)-3,5-dioxo-2,3,4,5-18 tetrahydro-1,2,4-triazine-6-carbonitrile 26 F la NO, Step 1 HN
40 40 ____________________________________________ =

Step 2 H ;, _____________ =
N NH2Step 3 HN

26a 26b 26c 26d I
Step 4 HN N NH

Step 1: Synthesis of 6-(2,6-dimethy1-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb 21 [00305] To a solution of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one la (3.0 g, 18 mmol) and 2-fluoro-1,3-22 dimethy1-5-nitrobenzene 26a (3.5 g, 21 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate 23 (2.8 g, 28 mmol), and the mixture was reacted at 80 C for 12 hours. The reaction solution was cooled to room 24 temperature, then water (150 mL) was added. The mixture was stirred for 10 minutes, and filtered. The filter cake was rinsed with water (30 mL >< 2), and the collected filter cake was slurried with ethyl acetate/petroleum ether (1/6, 26 70 mL). The mixture was filtered, and the filter cake was collected and dried to obtain a white solid 26b (4.2 g, 27 yield 73%).
28 Step 2: Synthesis of 6-(4-amino-2,6-dimethylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26c 29 [00306] To a solution of 6-(2,6-dimethy1-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26b (3.0 g, 9.6 mmol) in acetic acid (30 mL) was added iron powder (1.6 g, 29 mmol), and the mixture was reacted at 55 C for 5 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 hours. The reaction solution was cooled to room temperature, iron powder was removed, and ethyl acetate (200 mL) 2 was added. The mixture was washed with water (150 mL) and saturated sodium chloride solution (40 mL x 2) 3 successively, then dried over ahydrous sodium sulfate and concentrated by suction filtration. The resulting residue 4 was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give yellow oil 26e (2.7 g, yield 100%).
6 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dimethy1-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)phenyphydrazono)acetyl)carbamate 26d 8 [00307] To a solution of 6-(4-amino-2,6-methylphenoxy)-3,4-dihydroisoquinolin-1(2H)-one 26c (2.7 g, 9.6 9 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (1.0 g, 14 mmol) in water (5 mL) at 0 C. After reacting for 5 minutes, N-cyanoacetylurethane (1.9 g, 12 mmol) was added, and the mixture was reacted for 1.5 11 hours. At 0 C, water (10 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, 12 washed with water (5 mL), and the filter cake was collected and dried to obtain a yellow solid 26d (4.1 g, yield 13 95%).
14 Step 4: Synthesis of 2-(3,5-dimethy1-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 26 16 [00308] To a solution of ethyl (2-cyano-2-(2-(3,5-dimethy1-44(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)phenyphydrazono)acetyl)carbamate 26d (4.1 g, 9.1 mmol) in N,N-dimethylformamide (20 mL) was added 18 sodium acetate (0.90 g, 10 mmol), and the mixture was reacted at 120 C
for 7.5 hours. The reaction solution was 19 cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated sodium chloride solution (20 mL), dried over 21 anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue was separated and purified 22 by pre-HPLC [42%ACN/58%H20 (0.1%TFA), Kromasil specifications: C18 10 mx50mmx 250mm, flow rate:
23 100 mL/min] to obtain a white solid 26 (1.0 g, yield 27%, purity 95.48%).
24 MS (ESL, pos. ion) m/z: 404.2 [M+H]t 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.05 (s, 1H), 7.89 -7.72 (m, 211), 7.32 (s, 211), 6.76-6.61 (m, 311), 26 3.27-3.33 (m, 2H), 2.86 (t, J= 6.4 Hz, 2H), 2.11 (s, 6H).
27 Example 27 2-(3,5-dichloro-4-41-oxo-2-(p-toly1)-1,2,3,4-tetrahydroisoquinolin-6-ylloxylpheny1)-3,5-28 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 27 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 ci CI

Step 1 n N Step 2 N CI NO2 CI 1111111F NH 2 Step 3 0 = 0 27a 27b 27c CI CI
0 1"
0 0 ___________ 0 N,NN0õ,,,,, Step 4 = N
CI N NH

2 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(p-toly1)-3,4-dihydroisoquinolin-1(211)-one 27b 3 [00309] To a solution of 6-hydroxy-2-(p-toly1)-3,4-dihydroisoquinolin-1(211)-one 27a (refer to steps 1 and 2 4 of Example 23 of the patent application CN 109988109 A for the preparation method) (0.32 g, 1.3 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.34 g, 1.5 mmol) in N,N-dimethylformamide (6 mL) was added potassium carbonate 6 (0.35 g, 2.5 mmol), and the mixture was reacted at 60 C for 3 hours. The reaction solution was cooled to room 7 temperature, then water (8 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with 8 water (3 mL x 2). The filter cake was collected and dried to obtain a gray solid 27b (0.56 g, yield 99%).
9 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(p-toly1)-3,4-dihydroisoquinolin-1(211)-one 27c [00310] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(p-toly1)-3,4-dihydroisoquinolin-1(211)-one 27b 11 (0.56 g, 1.25 mmol) in acetic acid (5 mL) was added iron powder (0.21 g, 3.75 mmol), and the mixture was reacted 12 at 60 C for 5 hours. The reaction solution was cooled to room temperature, iron powder was removed, and water 13 (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic layers were 14 washed with saturated sodium chloride (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a white solid 27c (0.37 g, yield 72%).
16 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(p-toly1)-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)phenyphydrazono)acetyl)carbamate 27d 18 [00311] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(p-toly1)-3,4-dihydroisoquinolin-1(21-1)-one 19 27c (0.37 g, 0.90 mmol) in acetic acid (4 mL) was added N-cyanoacetylurethane (0.15 g, 1.08 mmol) at 0 C. The mixture was stirred for 5 minutes, then a solution of sodium nitrite (93 mg, 1.35 mmol) in water (1 mL) was added, 21 and the mixture was reacted for 1 hours. At 0 C, water (5 mL) was added to the reaction solution. The mixture was 22 stirred for 10 minutes, filtered, washed with water (3 mL), and the filter cake was collected and dried to obtain a 23 yellow solid 27d (0.50 g, yield 96%).
24 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(p-toly1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 27 26 [00312] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(p-toly1)-1,2,3,4-27 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 27d (0.50 g, 0.86 mmol) in N,N-28 dimethylformamide (6 mL) was added sodium acetate (0.14 g, 1.66 mmol), and the mixture was reacted at 120 C
29 for 3 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, the filter cake was collected and dried, and the obtained CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 solid was separated and purified by pre-HPLC [60%ACN/40%H20 (0.1% TFA), Kromasil Specifications: C18 m x5Omm x 250mm, flow rate: 100 mL/min] to obtain a white solid 27 (0.23 g, yield 50%, HPLC purity:
3 98.72%).
4 MS (ESL, neg. ion) m/z: 534.0 [M-H]-;
Ill NMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 1H).7.94 (d, J= 6.4 Hz, 1H), 7.86 (s, 2H), 7.24 (dd, J=23.6 6 Hz, J= 8.4 Hz, 4H), 6.97- 6.82 (m, 2H), 3.91 (t, J= 6.4 Hz, 2H), 3.11 (t, J= 6.8 Hz, 2H), 2.32 (s, 3H).
7 Example 28 2-(3,5-dichloro-4-01-oxo-2-(4-fluoropheny1)-1,2,3,4-tetrahydroisoquinolin-6-8 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile I o 0 1 st-,5a, 0 _ F F 0 Step 2 ja ' ---- 0 Step 3 ,,,----_, ,N
... , --' Step 4 CI

28a 28b F
28c F ..-.- 0 28d CI CI
CI

NC'',o, IIP iti CI
CI
F St C40 7o, 0 0 .5 0 ci õ N
,NA N jiõ,,, Step 6 H
illir 028e F

28f 28g CN
CI CI
' I 0 0 o 0 Step 7 N .....- _________ If .-ii, CI N NH Step 8 igh N I ..õ--CI N NH

F 1111111-1111 '0 F 0 NWil 9 28h COOH 28 Step 1: Synthesis of 2-(4-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(21-1)-one 28b [00313] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), sodium iodide (0.32 g, 1.7 mmol), 1-fluoro-4-iodobenzene (3.76 g, 16.9 mmol) and potassium carbonate (1.17 g, 8.47 mmol) were dissolved 13 in N,N-dimethylformamide (40 mL), and the mixture was reacted at 150 C for 16 hours. The reaction solution was cooled to room temperature, and water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), then dried over ahydrous sodium sulfate and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give an off-white solid 28b (1.05 g, yield 18 46%).

Ill NMR (400 MHz, CDC13) 8 (ppm) 8.11 (d, J= 8.6 Hz, 1H), 7.36 (ddt, J= 6.8, 4.9, 2.8 Hz, 2H), 7.16-7.08 (m, 2H), 6.90 (dd, J= 8.7, 2.6 Hz, 1H), 6.74 (d, J= 2.5 Hz, 1H), 3.96 (t, J=
6.4 Hz, 2H), 3.89 (s, 3H), 3.13 (t, J=
21 6.4 Hz, 2H).
22 Step 2: Synthesis of 2-(4-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 28c [00314] At 0 C, to a solution of 2-(4-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 28b (1.00 24 g, 3.7 mmol) in dichloromethane (30 mL) was added boron tribromide (0.71 mL, 7.4 mmol) dropwise. Then the mixture was reacted at room temperature for 4 hours. The reaction solution was quenched by pouring into ice water CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 (30 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and 2 the filter cake was collected and dried to obtain a white solid 28c (0.87 g, yield 92%).
3 MS (ESL, pos. ion) m/z: 258.1 [M+H]t 4 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 28d 6 [00315] To a solution of 2-(4-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 28c (0.87 g, 3.4 7 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.87 g, 3.8 mmol) in /V,N-dimethylformamide (15 mL) was added 8 potassium carbonate (0.93 g, 6.8 mmol), and the mixture was reacted at 70 C for 17 hours. The reaction solution 9 was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain an off-white solid 28d 11 (1.50 g, yield 99%).
12 MS (ESI, pos. ion) m/z: 448.0 [M+H].
13 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 14 28e 1003161 To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-fluoropheny1)-3,4-dihydroisoquinolin-1(21-1)-16 one 28d (1.50 g, 3.30 mmol) in acetic acid (20 mL) was added iron powder (0.37 g, 6.70 mmol), and the mixture 17 was reacted at 50 C for 3 hours. The reaction solution was cooled to room temperature, iron powder was removed, 18 and water (80 mL) was added. The mixture was extracted with ethyl acetate (80 mL x 2). The combined organic 19 layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 21 = 1/1) to give light yellow oil 28e (1.05 g, yield 75%).
22 MS (ESI, pos. ion) m/z: 417.1 [M+H].
23 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(4-fluoropheny1)-1-oxo-1,2,3,4-24 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetyl)carbamate 28f [00317] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-fluoropheny1)-3,4-dihydroisoquinolin-26 1(2H)-one 28e (1.00 g, 2.40 mmol) in acetic acid (36 mL) was added a solution of sodium nitrite (0.33 g, 4.8 mmol) 27 in water (18 mL) dropwise at 0 C. After reacting for 15 minutes, N-cyanoacetylurethane (0.56 g, 3.60 mmol) was 28 added, and the mixture was reacted for 5 hours. Water (50 mL) was added to the reaction solution. The mixture was 29 stirred for 10 minutes, filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 28f (1.30 g, yield 93%).
31 MS (ESL, pos. ion) m/z: 585.1 [M+H].
32 Step 6: Synthesis of 2-(3,5-dichloro-4-42-(4-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-33 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28g 34 [00318] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(4-fluoropheny1)-1-oxo-1,2,3,4-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 28f (1.30 g, 2.20 mmol) in N,N-2 dimethylformamide (40 mL) was added sodium acetate (0.40 g, 2.90 mmol), and the mixture was reacted at 120 C
3 for 15 hours. The reaction solution was cooled to room temperature, and water (80 mL) was added to quench the 4 reaction. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated by suction 6 filtration. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate), and the 7 obtained solid was recrystallized (petroleum ether/ethyl acetate = 1/2, 24 mL) at 80 C to obtain a yellow solid 28g 8 (0.71 g, yield 59%, HPLC purity: 97.86%).
9 MS (ESL, neg. ion) m/z: 537.1 [M-H];
IHNMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.86 (s, 2H), 7.43 (dd, J= 8.8, 11 5.0 Hz, 2H), 7.25 (t, J= 8.8 Hz, 2H), 6.95 (d, J= 2.6 Hz, 1H), 6.88 (dd, J= 8.6, 2.7 Hz, 1H), 3.93 (t, J= 6.4 Hz, 12 2H), 3.13 (t, J= 6.5 Hz, 2H).
13 Step 7: Synthesis of 2-(3,5-dichloro-44(2-(4-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 28h 1003191 2-(3,5-Dichloro-4-((2-(4-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-16 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 28g (0.45 g, 0.84 mmol) was dissolved in acetic acid (8 mL), 17 then concentrated hydrochloric acid (4 mL) was added. The mixture was reacted at 100 C for 17 hours. The reaction 18 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 19 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 28h (0.35 g, yield 75%).
21 Step 8: Synthesis of 2-(3,5-dichloro-4-((2-(4-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-22 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 28 23 [00320] 2-(3,5-Dichloro-442 -(4-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-24 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 28h (0.35 g, 0.63 mmol) was dissolved in thioglycolic acid (2.5 mL). The mixture was reacted at 140 C for 24 hours. The reaction solution was cooled to room temperature, 26 and ethyl acetate (60 mL) was added. The mixture was washed successively with water (20 mL), saturated sodium 27 bicarbonate solution (30 mL x 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium 28 sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 29 (petroleum ether/ethyl acetate = 1/3) to give a yellow solid 28 (0.21 g, yield 61%, HPLC purity: 96.79%).
MS (ESL, neg. ion) m/z: 514.1 [M+Hr;
31 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.52 (s, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.88 (s, 2H), 7.73 (s, 1H), 32 7.43 (dd, J= 8.9, 5.2 Hz, 2H), 7.24 (t, J= 8.8 Hz, 2H), 6.93 (d, J= 2.6 Hz, 1H), 6.85 (dd, J= 8.6, 2.6 Hz, 1H), 3.92 33 (t, J= 6.4 Hz, 2H), 3.13 (t, J= 6.4 Hz, 2H).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Example 29 2-(3,5-dichloro-4-41-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-2 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 29 a a oy F2C F3C
HIV- I CINO2 Step 1 4110 I CINO2 I CI I

Step 2 N. N Step 3 lb 29a 29b CI CI
CI
F3C .0 F3C 0 ,,,Np F3c 40 CI 11111111)11 NH 0 Step 4 40 CI N NH
Step 5 41111" CI PI NA' NH

NHCOOEt -LO 0 y 29c CN 29d CN
29e COOH
CI

UL2 'o 40 Step 6 JCI N JNH
0 "0 4 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzy1)-3,4-dihydroisoquinolin-1(211)-one 29a 6 [00321] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(21-1)-one lb (1.50 g, 4.2 7 mmol) in THF (20 mL) was added sodium hydride (0.25 mg, 6.3 mmol, 60 mass% in oil) at 0 C. After 30 minutes 8 of reaction, 1-bromomethy1-4-(trifluoromethyl)benzene (2.0 g, 8.37 mmol) and N,N-dimethylformamide (6 mL) 9 were added dropwise, and the mixture was reacted at room temperature for 3.5 hours. The reaction was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers 11 were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate and concentrated by 12 suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) 13 = 5/1) to give light yellow oil 29a (2.2 g, yield 100%).
14 MS (ESL pos. ion) m/z: 511.0 [M+H]t Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethyl)benzy1)-3,4-dihydroisoquinolin-16 1(211)-one 29b 17 [00322] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethyl)benzy1)-3,4-18 dihydroisoquinolin-1(21-1)-one 29a (2.2 g, 4.2 mmol) in acetic acid (50 mL) was added iron powder (0.99 g, 17.8 19 mmol), and the mixture was reacted at 55 C for 10 hours. The reaction solution was cooled to room temperature.
The reaction was quenched with water (100 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The 21 combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate 22 and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 23 ether/ethyl acetate (v/v) = 3/1) to give light yellow oil 29b (1.65 g, yield 77%).
24 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)phenyl)hydrazono)acetypcarbamate 29c 26 [00323] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethypbenzy1)-3,4-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 dihydroisoquinolin-1(2H)-one 29b (0.60 g, 1.25 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite 2 (0.19 g, 12.78 mmol) in water (6 mL) at 0 C, then AT-cyanoacetylurethane (0.26 g, 1.67 mmol) was added. The 3 mixture was reacted for 3 hours. Water (100 mL) was added to quench the reaction. The mixture was stirred for 20 4 minutes, filtered, and the filter cake was washed with water (5 mL X 2).
Then the filter cake was collected and dried to obtain a light yellow solid 29c (0.76 g, yield 94%).
6 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 29d 8 [00324] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-9 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 29c (0.72 g, 1.12 mmol) in N,N-dimethylformamide (25 mL) was added sodium acetate (0.20 g, 2.45 mmol), and the mixture was reacted at 120 C
11 for 6 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 12 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, 13 recrystallized (ethyl acetate/petroleum ether (v/v) = 2/1, 15 mL) at 80 C to obtain a yellow solid 29d (0.65 g, yield 14 97%, HPLC purity: 96.68%).
MS (ESL, neg. ion) in/z: 600.0 [M-H];
16 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.84(s, 2H), 7.71 (d, J= 8.0 17 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 6.88 (d, J= 2.6 Hz, 1H), 6.85 (dd, J=
8.3, 2.7 Hz, 1H), 4.78 (s, 2H), 3.53 (t, J =
18 6.6 Hz, 2H), 2.99 (t, J= 6.6 Hz, 2H).
19 Step 5: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 29e 21 [00325] 2-(3,5-Dichloro-4-((1 -oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-22 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 29d (0.65 g, 1.01 mmol) was dissolved in 23 acetic acid (10 mL), then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 120 C for 24 13 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and 26 dried to obtain a yellow solid 29e (0.55 g, yield 82%).
27 Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(4-(trifluoromethyl)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-28 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 29 29 [00326] 2-(3,5-Dichloro-4-((1 -oxo-2-(4-(trifluoromethypbenzy1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 29e (0.55 g, 0.89 mmol) was 31 dissolved in thioglycolic acid (5 mL). The mixture was reacted at 150 C
for 24 hours. The reaction solution was 32 cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water 33 (10 mL), saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), then dried 34 over anhydrous sodium sulfate and concentrated by suction filtration.
The resulting residue was purified by silica CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1), and the obtained solid was recrystallized at 2 70 C (ethyl acetate/methanol/petroleum ether (v/v/v) = 5/1/10, 32 mL) to give a white solid 29 (0.32 g, yield 62%, 3 HPLC purity: 96.97%).
4 MS (ESL, neg. ion) m/z: 575.0 [M-1-1]-;
11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.52 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.87 (s, 211), 7.73 (s, 1H), 6 7.70 (d, J= 7.9 Hz, 2H), 7.54 (d, J= 7.9 Hz, 2H), 6.85 (s, 1H), 6.84-6.79 (m, 1H), 4.78 (s, 2H), 3.52 (t, J= 6.5 Hz, 7 2H), 2.98 (t, J = 6.6 Hz, 2H).
8 Example 30 2-(3,5-diehloro-4-02-(3,4-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-9 yl)oxylpheny1)-1,2,4-triazine-3,5(2H,41/)-dione 30 ci ON<L1 g0- F
Step 3 N Step 2 *1 N -"/\..-")1, Step 1 F CI NO2 CI NI-12 1 b 30a 30b CI
CI
N
F
F Iga I36, C NH 0 Step 4 'F 41 Cõ I N NH Step 9 'F Ci N .. NH

IL)I'NHCOOEt 0 0 30a CN 30d oN
30e COOH
CI
F alb dight, 0 - tip CI 110 i Step 6 F N N NH0
30 11 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzy1)-3,4-dihydroisoquinolin-1 (211)-12 one 30a 13 [00327] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.00 g, 2.83 14 mmol) in THF (40 mL) was added sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) at 0 C. After 30 minutes of reaction, 3,4-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N,N-dimethylformamide (6 mL) were added 16 dropwise, and the mixture was reacted at room temperature for 12 hours.
The reaction was quenched with ice water 17 (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with 18 saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 19 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give light yellow oil 30a (1.10 g, yield 81%).
21 MS (ESL, pos. ion) m/z: 479.1 [M+H]t 22 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-23 one 30b 24 [00328] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3,4-difluorobenzy1)-3,4-dihydroisoquinolin-1(211)-one 30a (1.10 g, 2.29 mmol) in acetic acid (50 mL) was added iron powder (0.51 g, 9.15 mmol), and the CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 mixture was reacted at 55 C for 6 hours. The reaction solution was cooled to room temperature. The reaction was 2 quenched with water (80 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic 3 layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated 4 by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give light yellow oil 30b (0.64 g, yield 62%).
6 MS (ESL pos. ion) m/z: 431.0 [M+H]t 7 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(3,4-difluorobenzy1)-1-oxo-1,2,3,4-8 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 30c 9 [00329] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3,4-difluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 30b (0.65 g, 1.42 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (0.20 g, 2.90 11 mmol) in water (6 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.27 g, 1.71 mmol) was added. The mixture 12 was reacted for 2 hours. Water (100 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, 13 filtered, and the filter cake was washed with water (5 mL x 2). Then the filter cake was collected and dried to obtain 14 a light yellow solid 30c (0.94 g, yield 100%).
Step 4: Synthesis of 2-(3,5-dichloro-44(2-(3,4-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-16 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 30d 17 [00330] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(3,4-difluorobenzy1)-1-oxo-1,2,3,4-18 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 30c (0.94 g, 1.53 mmol) in N,N-19 dimethylformamide (30 mL) was added sodium acetate (0.28 g, 3.36 mmol), and the mixture was reacted at 120 C
for 6 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 21 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, 22 recrystallized (ethyl acetate/petroleum ether (v/v) = 2/1, 15 mL) at 80 C to obtain a yellow solid 30d (0.45 g, yield 23 52%, HPLC purity: 94.04%).
24 MS (ESL neg. ion) m/z: 550.0 [M-H]-;
'H NMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.84 (s, 2H), 7.39 (td, J= 7.9, 26 6.1 Hz, 111), 7.18-7.07 (m, 3H), 6.86 (s, 1H), 6.84 (d, J= 2.7 Hz, 1H), 4.70 (s, 2H), 3.51 (t, J= 6.6 Hz, 211), 2.97 27 (t, J= 6.6 Hz, 2H).
28 Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,4-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-29 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 30e [00331] 2-(3,5-Dichloro-442-(3,4-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-
31 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 30d (0.45 g, 0.79 mmol) was dissolved in acetic acid (6
32 mL), then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 12 hours. The
33 reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred
34 for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 solid 30e (0.41 g, yield 89%).
2 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(3,4-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-3 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,411)-dione 30 4 [00332] 2-(3,5-Dichloro-442-(3,4-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 30e (0.41 g, 0.68 mmol) was dissolved in thioglycolic 6 acid (3 mL). The mixture was reacted at 140 C for 19 hours. The reaction solution was cooled to room temperature, 7 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium 8 bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate 9 and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1), and the obtained solid was recrystallized at 70 C (ethyl acetate/methanol/petroleum 11 ether (v/v/v) = 5/1/10, 32 mL) to give a white solid 30 (0.25 g, yield 67%, HPLC purity: 93.81%).
12 MS (ESL, neg. ion) m/z: 543.0 [M-11]-;
13 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.52 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.87 (s, 2H), 7.72 (s, 1H), 14 7.45-7.32 (m, 2H), 7.18 (t, J= 6.4 Hz, 1H), 6.83 (s, 1H), 6.81 (d, J=
2.6 Hz, 1H), 4.66 (s, 2H), 3.50 (t, J= 6.5 Hz, 2H), 2.97 (t, J= 6.6 Hz, 2H).
16 Example 31 2-(3,5-dichloro-44(2-(3-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 31 ci oy-1,1 o Flri 'NO2 SI P F 11. N 111111-1 CI
4111111bil NO2 Step 2' N 101 Step 3 lb 31a 0 31b CI CI

CI NH 0 Step 4 F 0 __ 00 N 140 40 CI ___ N NH step 5 F ,N 0 NHCOOEt 0 N 0 N
31c CN 31d ON 31e COOH
CI
Step b F

____________________ 140 N 10 11 cy N" NH
N

19 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 31a 21 [00333] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.00 g, 2.83 22 mmol) in THF (14 mL) was added sodium hydride (0.17 g, 7.08 mmol, 60 mass% in oil). After 30 minutes of 23 reaction, 1-bromomethy1-3-fluorobenzene (1.07 g, 5.66 mmol) and /V,N-dimethylformamide (6 mL) were added 24 dropwise, and the mixture was reacted at room temperature for 3 hours.
The reaction was quenched with ice water (10 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with 26 saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to give light 2 yellow oil 31a (1.30 g, yield 99%).
3 MS (ESL, pos. ion) m/z: 461.1 [M+H]t 4 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 31b 6 [00334] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluorobenzy1)-3,4-dihydroisoquinolin-1(21-1)-7 one 31a (1.80 g, 3.90 mmol) in acetic acid (50 mL) was added iron powder (0.87 g, 15.2 mmol), and the mixture 8 was reacted at 55 C for 7 hours. The reaction solution was cooled to room temperature. The reaction was quenched 9 with water (80 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction 11 filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) 12 to give a white solid 31b (1.29 g, yield 77%).
13 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-fluorobenzy1)-1-oxo-1,2,3,4-14 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 31c [00335] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluorobenzy1)-3,4-dihydroisoquinolin-16 1(21/)-one 31b (0.60 g, 1.39 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite (0.19 g, 2.78 17 mmol) in water (5 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.26 g, 1.67 mmol) was added. The mixture 18 was reacted for 2 hours. Water (100 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, 19 filtered, and the filter cake was washed with water (5 mL x 2). Then the filter cake was collected and dried to obtain a light yellow solid 31c (0.92 g, yield 100%).
21 Step 4: Synthesis of 2-(3,5-dichloro-4-42-(3-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-22 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 31d 23 [00336] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-fluorobenzy1)-1-oxo-1,2,3,4-24 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 31c (0.92 g, 1.54 mmol) in N,N-dimethylformamide (30 mL) was added sodium acetate (0.28 g, 3.39 mmol), and the mixture was reacted at 120 C
26 for 6 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 27 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, 28 recrystallized (ethyl acetate/petroleum ether (v/v) = 2/1, 15 mL) at 80 C to obtain a yellow solid 31d (0.75 g, yield 29 99%) Step 5: Synthesis of 2-(3,5-dichloro-442-((3-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-31 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 31e 32 [00337] 2-(3,5-Dichloro-4-((2-(3-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-33 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 31d (0.39 g, 0.71 mmol) was dissolved in acetic acid (10 mL), 34 then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 12 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred for 10 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 2 31e (0.40 g, yield 98%).
3 Step 6: Synthesis of 2-(3,5-dichloro-44(243-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-4 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 31 [00338] 2(3,5-Dichloro-4((2-(3-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-6 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 31e (0.40 g, 0.70 mmol) was dissolved in thioglycolic acid 7 (3 mL). The mixture was reacted at 140 C for 19 hours. The reaction solution was cooled to room temperature, and 8 ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), and saturated sodium 9 bicarbonate solution (10 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1), and the 11 obtained solid was recrystallized at 70 C (ethyl acetate/methanol/petroleum ether (v/v/v) = 5/1/10, 32 mL) to give 12 a white solid 31 (0.20 g, yield 54%, HPLC purity: 93.81%).
13 MS (ESL neg. ion) m/z: 525.0[M-11]-;
14 'H NMR (400 MHz, DMSO-d6) 8(ppm) 12.52 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.86 (s, 2H), 7.73 (s, 1H), 7.38 (td, J= 7.9, 6.0 Hz, 111), 7.18- 7.06 (m, 3H), 6.86-6.77 (m, 2H), 4.69 (s, 2H), 3.50 (t, J= 6.5 Hz, 2H), 2.96 (t, J=
16 6.6 Hz, 2H).
17 Example 32 2-(3,5-dichloro-4-02-(3,5-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-18 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 32 CI CI CI
=0 rµi 0,e1 HN -.1..;õ)-(N
SI P F&N = CI NO, Step 2 41111-. 1 CI)-CNH2 Step 3 0 lb 032a 32b CI

,N
CI NH 0 Step 4 F 0 .. 40 ,/,1 =
c, J.L
N NH Step 5 'F

____________________________________________________________________ 101 ,N

NNH
0N)INHCQQEt 0 0 11 rLID
32c CN 32d CN 32e COON

Step N

Step 1: Synthesis of 2-(3,5-difluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(210-21 one 32a 22 [00339] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.0 g, 2.83 23 mmol) in THF (14 mL) was added sodium hydride (0.17 g, 4.25 mmol, 60 mass% in oil) at 0 C. After 20 minutes 24 of reaction, 3,5-difluorobenzyl bromide (1.17 g, 5.66 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, and the mixture was reacted at room temperature for 6 hours. The reaction was quenched with ice water 26 (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 2 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give light 3 yellow oil 32a (1.26 g, yield 93%).
4 MS (ESL, pos. ion) m/z: 480.1 [M+H]t Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-6 one 32b 7 [00340] To a solution of 2-(3,5-difluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-8 1(2H)-one 32a (0.99 g, 2.1 mmol) in acetic acid (20 mL) was added iron powder (0.24 g, 4.3 mmol), and the mixture 9 was reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature. The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2).
The combined organic layers were 11 washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction 12 filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) 13 to give light yellow oil 32b (0.68 g, yield 58%).
14 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3,5-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 32c 16 [00341] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3,5-difluorobenzy1)-3,4-dihydroisoquinolin-17 1(211)-one 32h (0.68 g, 1.5 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.21 g, 3.0 mmol) 18 in water (9 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.35 g, 2.3 mmol) was added. The mixture was 19 reacted for 3 hours. Water (60 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). Then the filter cake was collected and dried to obtain a 21 light yellow solid 32c (0.93 g, yield 100%).
22 MS (ESL, neg. ion) m/z: 615.2 [M-H].
23 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(3,5-difluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-24 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 32d [00342] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3,5-difluorobenzy1)-1-oxo-1,2,3,4-26 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 32c (0.93 g, 1.5 mmol) in N,N-27 dimethylformamide (16 mL) was added sodium acetate trihydrate (0.27 g, 2.0 mmol), and the mixture was reacted 28 at 120 C for 8 hours. The reaction solution was cooled to room temperature, then water (50 mL) was added to 29 quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and dried, recrystallized (ethyl acetate/petroleum ether (v/v) = 2/1, 30 mL) at 80 C to obtain a yellow solid 32d (0.63 g, 31 yield 73%, HPLC purity: 95.85%).
32 MS (ESL, neg. ion) m/z: 571.3 [M-H];
33 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 13.27 (s, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.84 (s, 2H), 7.12 (td, J = 9.4, 34 4.8 Hz, 1H), 7.03 (d, J= 7.3 Hz, 2H), 6.91-6.76 (m, 2H), 4.69 (s, 2H), 3.53 (t, J= 6.6 Hz, 2H), 2.99 (t, J= 6.6 Hz, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 2H).
2 Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((3,5-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-3 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 32e 4 [00343] 2-(3,5-Dichloro-442-(3,5-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 32d (0.55 g, 0.96 mmol) was dissolved in acetic acid (10 6 mL), then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 8 hours. The 7 reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred 8 for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow 9 solid 32e (0.48 g, yield 84%).
MS (ESL, pos. ion) m/z: 590.0 [M+H].
11 Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3,4-difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-12 yfloxy)pheny1)-1,2,4-triazine-3,5(2H,411)-dione 32 13 [00344] 243,5 -Dichloro-442 -(3,5 -difluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-y0oxy)pheny1)-14 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 32e (0.48 g, 0.81 mmol) was dissolved in thioglycolic acid (5 mL). The mixture was reacted at 140 C for 16 hours. The reaction solution was cooled to room temperature, 16 and ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution 17 (30 mL x 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and concentrated 18 by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 19 (v/v) = 3/2), and the obtained solid was recrystallized at 80 C (ethyl acetate/petroleum ether (v/v) = 1/2, 30 mL) to give a light yellow solid 32 (0.20 g, yield 45%, HPLC purity: 99.48%).
21 MS (ESL, neg. ion) m/z: 544.2 [M-11]-;
22 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.51 (s, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 23 7.12 (tt, J= 9.4, 2.5 Hz, 1H), 7.06-6.96 (m, 2H), 6.87-6.78 (m, 2H), 4.69 (s, 2H), 3.53 (t, J= 6.6 Hz, 2H), 2.98 (t, J
24 = 6.6 Hz, 2H).
Example 33 2-(3,5-dichloro-4-((2-(2-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-26 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 33 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 ci ci H N Stop 1 N= CI CI'113.-- Stop 3 NO2 Stop 2 N

lb 33a 33b CI CI

N 00. N Ao CI NH 0 Step 4 = CI N NH Step 5 Nh1IJfJCI N-KNH
0 N ,},NHCOOEt N
gl õ
-r -0 33c CN 33d CN 33e COOH
CI

A
Step 6 N 1111111 CI -***- N NH

2 Step 1: Synthesis of 2-(2-fluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 3 33a 4 [00345] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.0 g, 2.8 mmol) in THF (40 mL) was added sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) at 0 C. After 20 minutes of 6 reaction, 2-fluorobenzyl bromide (1.1 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, 7 and the mixture was reacted at room temperature for 6 hours. The reaction was quenched with ice water (30 mL).
8 The mixture was extracted with ethyl acetate (30 mL X 2). The combined organic layers were washed with saturated 9 sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give a light yellow 11 solid 33a (0.99 g, yield 76%).
12 MS (ESL, pos. ion) m/z: 461.1 [M+H]t 13 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 14 33b [00346] To a solution of 2-(2-fluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-16 one 33a (0.99 g, 2.1 mmol) in acetic acid (20 mL) was added iron powder (0.24 g, 4.3 mmol), and the mixture was 17 reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature. The reaction was quenched 18 with water (30 mL). The mixture was extracted with ethyl acetate (50 mL
X 2). The combined organic layers were 19 washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) 21 to give light yellow oil 33b (0.62 g, yield 67%).
22 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(2-fluorobenzy1)-1-oxo-1,2,3,4-23 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 33c 24 [00347] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluorobenzy1)-3,4-dihydroisoquinolin-1(21/)-one 33b (0.62 g, 1.4 mmol) in acetic acid (18 mL) was added a solution of sodium nitrite (0.20 g, 2.9 mmol) 26 in water (9 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.34 g, 2.2 mmol) was added. The mixture was 27 reacted for 3 hours. Water (50 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 filtered, and the filter cake was washed with water (10 mL). Then the filter cake was collected and dried to obtain a 2 light yellow solid 33c (0.86 g, yield 100%).
3 MS (ESL, neg. ion) m/z: 599.2 [M-11]-.
4 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(2-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 33d 6 [00348] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(2-fluorobenzy1)-1-oxo-1,2,3,4-7 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 33c (0.86 g, 1.4 mmol) in N,N-8 dimethylformamide (16 mL) was added sodium acetate trihydrate (0.26 g, 1.9 mmol), and the mixture was reacted 9 at 120 C for 6 hours. The reaction solution was cooled to room temperature, then water (50 mL) was added to quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and 11 dried, recrystallized (ethyl acetate/petroleum ether (v/v) = 2/1, 30 mL) at 80 C to obtain a yellow solid 33d (0.49 g, 12 yield 63%, HPLC purity: 96.04%).
13 MS (ESI, pos. ion) m/z: 553.0 [M+H];
14 IHNMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 7.91 (d, J= 8.3 Hz, 1H), 7.83 (s, 2H), 7.34 (qd, J= 6.8, 5.8, 3.3 Hz, 2H), 7.26-7.10 (m, 2H), 6.92-6.80 (m, 2H), 4.73 (s, 2H), 3.52 (t, J= 6.6 Hz, 2H), 2.98 (t, J= 6.5 Hz, 16 2H).
17 Step 5: Synthesis of 2-(3,5-dichloro-4-((2-((2-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-18 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 33e 19 [00349] 2-(3,5-Dichloro-442-(2-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 33d (0.43 g, 0.78 mmol) was dissolved in acetic acid (10 mL), 21 then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 8 hours. The reaction 22 solution was cooled to room temperature, then water (30 mL) was added.
The reaction mixture was stirred for 10 23 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 24 33e (0.38 g, yield 85%).
MS (ESL, pos. ion) m/z: 572.0 [M+H]t 26 Step 6: Synthesis of 2-(3,5-dichloro-4-42-(2-fl uorobenzy1)-1 -oxo-1,2,3,4-tetrahydroi soqui nol in-6-27 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 33 28 [00350] 2-(3,5-Dichloro-442-(2-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-29 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 33e (0.38 g, 0.66 mmol) was dissolved in thioglycolic acid (5 mL). The mixture was reacted at 140 C for 16 hours. The reaction solution was cooled to room temperature, and 31 ethyl acetate (60 mL) was added. The mixture was washed successively with 50% sodium bicarbonate solution (30 32 mL x 2) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and concentrated by 33 suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) 34 = 3/2), and the obtained solid was recrystallized at 80 C (ethyl acetate/petroleum ether (v/v) = 1/2, 30 mL) to give CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 a light yellow solid 33 (0.29 g, yield 83%, HPLC purity: 99.47%).
2 MS (ESL pos. ion) m/z: 527.0 [M+Hr;

111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.51 (s, 1H), 7.91 (d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 7.33 (q, J= 7.8 Hz, 2H), 7.24-7.12 (m, 2H), 6.87-6.78 (m, 2H), 4.73 (s, 2H), 3.52 (t, J= 6.6 Hz, 2H), 2.97 (t, J=
6.5 Hz, 2H).

Example 34 2-(3,5-diehloro-4-42-(3-(trifluoromethyl)benzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,411)-dione 34 0 di f HN Step -NO2 Stq' F,C 411L-NrICI 11111" NO2 SWP 2 F3C CI:b: 'NH2 lb 34a 34b CI CI
CI

jj N)INHCOOEt 40 co - )3, __________ 40 N
FaC CI NH =

0 Step 4 F3C CI N
NH st3p 5 F3C CI' N NH
0 "1,A0 0 34c CN 34d CN 34e COOH
CI
Step 6 N CI N NH
No 9 Step 1: Synthesis of 2-(3-(trifluoromethypbenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 34a [00351] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.0 g, 2.8 mmol) in THF (40 mL) was added sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) at 0 C. After 20 minutes of reaction, 3-trifluoromethylbenzyl bromide (1.4 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added dropwise, and the mixture was reacted at room temperature for 6 hours. The reaction was quenched with ice water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give light 18 yellow oil 34a (0.86 g, yield 59%).
19 MS (ESL, neg. ion) m/z: 647.1 [M-H].
Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethypbenzy1)-3,4-dihydroisoquinolin-21 1(2H)-one 34b 22 [00352] To a solution of 2-(3-(trifluoromethyl)benzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 34a (0.86 g, 1.7 mmol) in acetic acid (20 mL) was added iron powder (0.24 g, 4.3 mmol), and the mixture was reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature.
The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate 2 and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 3 ether/ethyl acetate (v/v) = 1/2) to give light yellow oil 34b (0.63 g, yield 78%).
4 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-(trifluoromethypbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 34c 6 [00353] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethyl)benzy1)-3,4-7 dihydroisoquinolin-1(2H)-one 34h (0.63 g, 1.3 mmol) in acetic acid (18 mL) was added a solution of sodium nitrite 8 (0.18 g, 2.6 mmol) in water (9 mL) at 0 C, then N-cyanoacetylurethane (0.31 g, 2.0 mmol) was added. The mixture 9 was reacted for 3 hours. Water (50 mL) was added to quench the reaction.
The mixture was stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). Then the filter cake was collected and dried to obtain a 11 light yellow solid 34c (0.85 g, yield 100%).
12 MS (ESL, neg. ion) m/z: 647.1 [M-H].
13 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(3-(trifluoromethyl)benzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 34d [00354] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-(trifluoromethypbenzy1)-1-oxo-1,2,3,4-16 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 34c (0.85 g, 1.3 mmol) in N,N-17 dimethylformamide (16 mL) was added sodium acetate trihydrate (0.23 g, 1.7 mmol), and the mixture was reacted 18 at 120 C for 6 hours. The reaction solution was cooled to room temperature, then water (50 mL) was added to 19 quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and dried, recrystallized (ethyl acetate/petroleum ether (v/v) = 1/2, 30 mL) at 80 C to obtain a yellow solid 34d (0.55 g, 21 yield 70%, HPLC purity: 97.82%).
22 MS (ESL, neg. ion) m/z: 601.3 [M-H];
23 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.84 (s, 2H), 7.72-7.55 (m, 24 4H), 6.85 (d, J = 8.8 Hz, 2H), 4.77 (s, 211), 3.52 (t, J= 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H).
Step 5: Synthesis of 2-(3,5-dichloro-44(2-(3 -(trifluoromethyl)benzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-26 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 34e 27 [00355] 2-(3,5-Dichloro-4-((2-(3-(trifluoromethyl)benzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-28 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 34d (0.47 g, 0.80 mmol) was dissolved in 29 acetic acid (10 mL), then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 8 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture 31 was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2).
The filter cake was collected and dried to 32 obtain a yellow solid 34e (0.43 g, yield 89%).
33 MS (ESL, neg. ion) m/z: 622.0 [M-H]-.
34 Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-(trifluoromethyl)benzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 34 2 [00356] 2-(3,5-Dichloro-4-((2-(3-(trifluoromethyl)benzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-3 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 34e (0.43 g, 0.71 mmol) was 4 dissolved in thioglycolic acid (5 mL). The mixture was reacted at 140 C
for 15 hours. The reaction solution was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50%
6 sodium bicarbonate solution (30 mL x 2) and saturated sodium chloride solution (30 mL), dried over anhydrous 7 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 8 (petroleum ether/ethyl acetate (v/v) = 3/2), and the obtained solid was recrystallized at 80 C (ethyl acetate/petroleum 9 ether (v/v) = 1/2, 30 mL) to give a light yellow solid 34 (0.24 g, yield 60%, HPLC purity: 99.41%).
MS (ESL, neg. ion) m/z: 576.0 [M-H]-;
11 '11 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.51 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 12 7.69-7.54 (m, 4H), 6.88-6.77 (m, 2H), 4.77 (s, 2H), 3.52 (t, J= 6.6 Hz, 2H), 2.96 (t, J= 6.5 Hz, 2H).
13 Example 35 2-(3,5-dichloro-4-02-(3-ehloro-4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 35 0 Ail F Aim 0,(1.,1 0 4/46, HNI?...).-% VP NO Step 1 a 4110 11; RIP No, Step 2 NH2 Step 3 1 b 35a 0 35b CI
CI

bc0'1C3 40 ________________________________________ ;o,c1 40 F -- I NH 0 Step 4 CI N NH sup 5 CI CI N NH

NHCOOEt 0 IrLO 0 35c CN 35d CN 35e COON
CI
Step 6 01 ) ,L
CI N NH
35 16 Step 1: Synthesis of 2-(3-chloro-4-fluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-17 1(211)-one 35a 18 [00357] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.0 g, 2.8 19 mmol) in THF (40 mL) was added sodium hydride (0.17 g, 4.2 mmol, 60 mass% in oil) at 0 C. After 20 minutes of reaction, 3-chloro-4-fluorobenzyl bromide (1.3 g, 5.7 mmol) and N,N-dimethylformamide (10 mL) were added 21 dropwise, and the mixture was reacted at room temperature for 6 hours.
The reaction was quenched with ice water 22 (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with 23 saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 24 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give a light yellow solid 35a (1.0 g, yield 71%).
26 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzy1)-3,4-dihydroisoquinolin-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 1(211)-one 35b 2 [00358] To a solution of 2-(3-chloro-4-fluorobenzy1)-6-(2,6-dichloro-4-nitrophenoxy)-3,4-3 dihydroisoquinolin-1(211)-one 35a (0.99 g, 2.0 mmol) in acetic acid (20 mL) was added iron powder (0.22 g, 4.0 4 mmol), and the mixture was reacted at 50 C for 2.5 hours. The reaction solution was cooled to room temperature.
The reaction was quenched with water (30 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The 6 combined organic layers were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate 7 and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 8 ether/ethyl acetate (v/v) = 1/2) to give light yellow oil 35b (0.61 g, yield 66%).
9 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(3-chloro-4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 35c 11 [00359] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-chloro-4-fluorobenzy1)-3,4-12 dihydroisoquinolin-1(211)-one 35b (0.61 g, 1.3 mmol) in acetic acid (18 mL) was added a solution of sodium nitrite 13 (0.18 g, 2.6 mmol) in water (9 mL) dropwise at 0 C, then N-cyanoacetylurethane (0.31 g, 2.0 mmol) was added.
14 The mixture was reacted for 3 hours. Water (50 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). Then the filter cake was collected and dried 16 to obtain a light yellow solid 35c (0.83 g, yield 100%).
17 MS (ESL, neg. ion) m/z: 631.1 [M-H]-.
18 Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-19 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 35d [00360] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-chloro-4-fluorobenzy1)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 35c (0.83 g, 1.3 mmol) in N,N-22 dimethylformamide (16 mL) was added sodium acetate trihydrate (0.23 g, 1.7 mmol), and the mixture was reacted 23 at 120 C for 6 hours. The reaction solution was cooled to room temperature, then water (50 mL) was added to 24 quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and dried, recrystallized (ethyl acetate/petroleum ether (v/v) = 1/2, 30 mL) at 80 C to obtain a yellow solid 35d (0.57 g, 26 yield 74%, HPLC purity: 93.07%).
27 MS (ESL, neg. ion) m/z: 585.0 [M-H]-;
28 1HNMR (400 MHz, DMSO-d6) 8 (ppm) 13.28 (s, 1H), 7.92 (d, J= 8.3 Hz, 1H), 7.83 (s, 2H), 7.53 (dd, J= 7.3, 29 2.1 Hz, 1H), 7.41-7.30 (m, 2H), 6.84 (d, J= 8.5 Hz, 2H), 4.66 (s, 2H), 3.51 (t, J= 6.6 Hz, 2H), 2.96 (t, J= 6.6 Hz, 2H).
31 Step 5: Synthesis of 2-(3,5-dichloro-4-42((3-chloro-4-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-32 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 35e 33 [00361] 2-(3,5-Dichloro-442-(3-chloro-4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-34 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 35d (0.47 g, 0.80 mmol) was dissolved in CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 acetic acid (10 mL), then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 2 8 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture 3 was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2).
The filter cake was collected and dried to 4 obtain a light yellow solid 35e (0.43 g, yield 89%).
MS (ESL, pos. ion) m/z: 606.9 [M+H]t 6 Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(3-chloro-4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 35 8 [00362] 243,5 -Dichloro-4-((2 -(3 -chloro-4-fluorobenzy1)-1-oxo-1,2,3,4 -tetrahydroisoquinolin-6-9 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 35e (0.43 g, 0.71 mmol) was dissolved in thioglycolic acid (5 mL). The mixture was reacted at 140 C for 15 hours. The reaction solution was 11 cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was washed successively with 50%
12 sodium bicarbonate solution (30 mL x 2) and saturated sodium chloride solution (30 mL), dried over anhydrous 13 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 14 (petroleum ether/ethyl acetate (v/v) = 3/2), and the obtained solid was recrystallized at 80 C (ethyl acetate/petroleum ether (v/v) = 1/2, 30 mL) to give a light yellow solid 35 (0.26 g, yield 65%, HPLC purity: 98.66%).
16 MS (ESL, neg. ion) m/z: 561.1 [M-11]-;
17 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.51 (s, 1H), 7.92 (d, J= 8.3 Hz, 1H), 7.86 (s, 2H), 7.72 (s, 1H), 18 7.52 (dd, J= 7.2, 2.0 Hz, 1H), 7.41-7.30 (m, 2H), 6.81 (d, J= 8.8 Hz, 2H), 4.66 (s, 2H), 3.50 (t, J= 6.6 Hz, 2H), 19 2.96 (t, J= 6.6 Hz, 2H).
Example 36 2-(3,5-diehloro-442-(3-methoxybenzy1)-l-oxo-1,2,3,4-tetrahydroisoquinolin-6-21 yl)oxy)pheny1)l,2,4-triazine-3,5(2H,411)-dione 36 Hriv-111,1 -7:1) Step 1 meyr...),,Nyl _No, Step 2 meo,C XII NH, Step 3 0 8 36b lb See CI CI
CI
Nf f Niffi;
Me0 Cr- NH 0 Step 4 Me0 CI' 3-1' N' 'NH
Step NHCOOEt 8 y 0 8 36c CN 36d CN
36e COOH
CI
run Step b CINNH

23 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-methoxybenzy1)-3,4-dihydroisoquinolin-1(2H)-24 one 36a [00363] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.8 g, 5.1 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 mmol) in THF (35 mL) was added sodium hydride (0.18 g, 7.6 mmol, 60 mass%
in oil) at 0 C. After 5 minutes of 2 reaction, 1-bromomethy1-3-methoxybenzene (1.0 g, 5.0 mmol) was added dropwise, and the mixture was reacted at 3 room temperature for 8 hours. The reaction was quenched with ice water (20 mL). The mixture was extracted with 4 ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column 6 chromatography (petroleum ether/ethyl acetate = 3/1) to give a white solid 36a (1.9 g, yield 79%).
7 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzy1)-3,4-dihydroisoquinolin-1(21-1)-8 one 36b 9 [00364] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-methoxybenzy1)-3,4-dihydroisoquinolin-1(211)-one 36a (1.9 g, 4.0 mmol) in acetic acid (7 mL) was added iron powder (0.67 g, 12 mmol), and the mixture 11 was reacted at 60 C for 4 hours. The reaction solution was cooled to room temperature, then water (5 mL) was 12 added to quench the reaction. The excess iron powder was filtered off, and water (10 mL) was added to the filtrate.
13 The mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected 14 and dried to obtain a brown solid 36b (1.7 g, yield 93%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-methoxybenzy1)-1-oxo-1,2,3,4-16 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 36c 17 [00365] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-methoxybenzy1)-3,4-dihydroisoquinolin-18 1(211)-one 36b (1.65 g, 3.72 mmol) in acetic acid (6 mL) was added a solution of sodium nitrite (0.39 g, 5.58 mmol) 19 in water (3 mL) at 0 C, then N-cyanoacetylurethane (0.86 g, 4.65 mmol) was added. The mixture was reacted for 1 hours. Water (20 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, and the 21 filter cake was washed with water (5 mL x 2). Then the filter cake was collected and dried to obtain a yellow solid 22 36c (2.1 g, yield 92%).
23 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(3 -methoxybenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-24 yl)oxy)pheny1)-3,5 -dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 36d [00366] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(3-methoxybenzy1)-1-oxo-1,2,3,4-26 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetyl)carbamate 36c (2.10 g, 3.40 mmol) in 1V,IV-27 dimethylformamide (8 mL) was added sodium acetate (0.34 g, 3.39 mmol), and the mixture was reacted at 120 C
28 for 12 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 29 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, recrystallized (ethyl acetate/petroleum ether = 2/1, 15 mL) at 80 C to obtain a yellow solid 36d (0.75 g, yield 99%) 31 Step 5: Synthesis of 2-(3,5-dichloro-44(243-methoxybenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-32 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 36e 33 [00367] 243,5 -Dichloro-442 -(3 -methoxybenzy1)-1-oxo-1,2,3,4 -tetrahydroisoquinolin-6-ypoxy)pheny1)-34 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 36d (0.45 g, 0.80 mmol) was dissolved in acetic acid (6 mL), then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 16 hours. The CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 reaction solution was cooled to room temperature, then water (10 mL) was added. The reaction mixture was stirred 2 for 10 minutes, filtered, and rinsed with water (5 mL X 2). The filter cake was collected and dried to obtain a yellow 3 solid 36e (0.40 g, yield 86%).
4 Step 6: Synthesis of 2-(3,5-dichloro-44(243 -methoxybenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 36 6 [00368] 2-(3,5-Dichloro-442-(3-methoxybenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-7 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 36e (0.40 g, 0.69 mmol) was dissolved in thioglycolic 8 acid (4 mL). The mixture was reacted at 160 C for 12 hours. The reaction solution was cooled to room temperature, 9 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration.
11 The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1) to give a white 12 solid 36 (39 mg, yield 11%, HPLC purity: 94.35%).
13 MS (ESI, neg. ion) m/z: 537.1[M-I-1]-;
14 'H NMR (400 MHz, DMSO-d6) 6 (,pm) 12.52 (s, 1H), 8.00-7.82 (m, 3H), 7.73 (s, 1H), 7.25 (t, J= 7.6 Hz, 1H), 6.97-6.77 (m, 5H), 4.66 (s, 2H), 3.73 (s, 3H), 3.46 (t, J= 6.4 Hz, 2H), 2.94 (t, J= 6.4 Hz, 2H).
16 Example 37 2-(3,5-dichloro-442-(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 37 H =

0,1 NO2 a=

o o -, I _________________________________________________ -N al CI,7 N Swp 2 N ..--Step 3 4111111"

0 lb 037a 0 37b CI

CI NH 0 Step CI 4 40 YL
N NH step 5 .
N 'JD
CI N NH

37c CN 37d oN
37e COOH
CI
c 1 a 0 x ) Step 6 N11 y NANH

19 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 37a 21 [00369] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(211)-one lb (3.0 g, 8.5 22 mmol) in THF (35 mL) was added sodium hydride (0.31 g, 13.0 mmol, 60 mass% in oil) at 0 C. After 5 minutes of 23 reaction, 1-chloromethy1-4-chlorobenzene (2.7 g, 17.0 mmol) was added dropwise, and the mixture was reacted at 24 room temperature for 8 hours. The reaction was quenched with ice water (20 mL). The mixture was extracted with ethyl acetate (20 mL X 2), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue 26 was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give a white solid 37a CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 (1.75 g, yield 43%).
2 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-chlorobenzy1)-3,4-dihydroisoquinolin-1(211)-one 3 37b 4 [00370] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-chlorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 37a (1.75 g, 3.66 mmol) in acetic acid (7 mL) was added iron powder (0.61 g, 11.0 mmol), and the mixture was 6 reacted at 60 C for 4.5 hours. The reaction solution was cooled to room temperature, then water (5 mL) was added 7 to quench the reaction. The excess iron powder was filtered off, and water (10 mL) was added to the filtrate. The 8 mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried 9 to obtain a brown solid 37b (1.55 g, yield 95%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(4-chlorobenzy1)- I
-oxo-1,2,3,4-11 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 37c 12 [00371] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-chlorobenzy1)-3,4-dihydroisoquinolin-13 1(211)-one 37b (1.55 g, 3.46 mmol) in acetic acid (6 mL) was added a solution of sodium nitrite (0.36 g, 5.25 mmol) 14 in water (3 mL) at 0 C, then N-cyanoacetylurethane (0.81 g, 4.37 mmol) was added. The mixture was reacted for 1 hours. Water (20 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, and the 16 filter cake was washed with water (5 mL). Then the filter cake was collected and dried to obtain a yellow solid 37c 17 (1.90 g, yield 89%).
18 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-19 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 37d [00372] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(4-chlorobenzy1)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 37c (1.9 g, 3.1 mmol) in N,N-22 dimethylformamide (8 mL) was added sodium acetate (0.30 g, 3.7 mmol), and the mixture was reacted at 120 C for 23 12 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 24 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, recrystallized (ethyl acetate/petroleum ether = 2/1, 15 mL) at 80 C to obtain a yellow solid 37d (0.50 g, yield 28%, 26 1-1PLC purity: 95.83%).
27 MS (ESL, neg. ion) m/z: 566.0 [M-1-1]-;
28 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.32 (s, 1H), 8.03-7.76 (m, 3H), 7.49-7.25 (m, 411), 6.94-6.76 (m, 29 2H), 4.68 (s, 2H), 3.48 (t, J= 6.4 Hz, 2H), 2.96 (t, J= 6.4 Hz, 2H).
Step 5: Synthesis of 2-(3,5-dichloro-44(2-(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-31 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 37e 32 [00373] 243,5 -Dichloro-442 -(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-33 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 37d (0.40 g, 0.70 mmol) was dissolved in acetic acid (6 mL), 34 then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 17 hours. The reaction CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 solution was cooled to room temperature, then water (10 mL) was added.
The reaction mixture was stirred for 10 2 minutes, filtered, and rinsed with water (5 mL x 2). The filter cake was collected and dried to obtain a yellow solid 3 37e (0.40 g, yield 97%).
4 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 37 6 [00374] 2-(3,5-Dichloro-442-(4-chlorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-7 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 37e (0.15 g, 0.26 mmol) was dissolved in thioglycolic acid 8 (3 mL). The mixture was reacted at 160 C for 12 hours. The reaction solution was cooled to room temperature, and 9 ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL), saturated sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate 11 and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 12 ether/ethyl acetate = 1/1) to give a white solid 37 (0.14 g, yield 38%, HPLC purity: 97.64%).
13 MS (ESI, neg. ion) m/z: 541.0 [M-I-1]-;
14 'H NMR (400 MHz, DMSO-d6) 6 (ppm) 12.52 (s, 1H), 8.01-7.80 (m, 3H), 7.73 (s, 1H), 7.46-7.26 (m, 4H), 6.90-6.74 (m, 2H), 4.68 (s, 2H), 3.48 (t, J= 6.8 Hz, 2H), 2.95 (t, J= 6.8 Hz, 2H).
16 Example 38 2-(3,5-dichloro-442-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonibile CI
0, , - 0 N, Step I Step 2 OH Step 3 CI
N 02 Step 4 5a 38a 38b 38c CI

CI

, A, I
1t CI, NH 0 Step 6 CI NH2 St" 5 0 'NHCOOEt 0 18 38d 38e CN 38 CN
19 Step 1: Synthesis of 6-methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38a [00375] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (2.5 g, 14.1 mmol) was dissolved in a mixture 21 solution of THF (30 mL) and N,N-dimethylacetamide (30 mL). Sodium hydride (1.41 g, 35.3 mmol, 60% in oil) 22 was added in portions at 0 C, then chloromethylcyclopropane (2.60 mL, 28.0 mmol) was added dropwise and N,N-23 dimethylformamide (30 mL) was added in turn. After the addition was complete, the reaction was continued at room 24 temperature for 24 hours. The reaction was quenched with water (40 mL).
The mixture was extracted with ethyl acetate (45 mL >< 3). The combined organic layers were washed with saturated sodium chloride (40 mL >< 3), dried 26 over anhydrous sodium sulfate and concentrated by suction filtration.
The residue was purified by silica gel column 27 chromatography (petroleum ether/ethyl acetate = 2/1) to give light yellow oil 38a (2.56 g, yield 78%).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 MS (ESI, pos. ion) m/z: 232.2 [M+H].
2 Step 2: Synthesis of 6-hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38a 3 [00376] 6-Methoxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38a (2.40 g, 10.4 mmol) was 4 dissolved in dichloromethane (35 mL). Boron tribromide (2.02 mL, 20.8 mmol) was slowly added dropwise at 0 C
and the mixture was reacted at 0 C for 1.5 hours. The reaction was quenched by adding methanol (5 mL) at 0 C.
6 The mixture was concentrated, and water (50 mL) was added. The mixture was extracted with ethyl acetate (30 mL
7 x 3). The combined organic layers were washed with saturated sodium chloride (30 mL x 2), dried over ahydrous 8 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 9 (petroleum ether/ethyl acetate = 2/1) to give a light yellow solid 38b (1.01 g, yield 45%).
Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-11 one 38c 12 [00377] To a solution of 6-hydroxy-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38b (1.01 g, 13 4.65 mmol) in /V,N-dimethylformamide (10 mL) were added 1,2,3-trichloro-5-nitrobenzene (1.11 g, 4.90 mmol) and 14 potassium carbonate (1.56 g, 11.2 mmol), and the mixture was reacted at 80 C for 6 hours. The reaction solution was cooled to room temperature, and water (15 mL) was added. The mixture was extracted with ethyl acetate (15 16 mL x 3). The combined organic layers were washed with saturated sodium chloride (15 mL x 3), dried over ahydrous 17 sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 18 (petroleum ether/ethyl acetate = 2/1) to give a yellow solid 38c (0.96 g, yield 51%).
19 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38d 21 [00378] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-22 1(2H)-one 38c (0.91 g, 2.23 mmol) in acetic acid (15 mL) was added iron powder (0.51 g, 8.93 mmol), and the 23 mixture was reacted at 60 C for 6.5 hours. The reaction solution was cooled to room temperature, iron powder was 24 removed, then water (25 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a light yellow solid 38d (0.72 g, yield 86%).
26 MS (ESL, pos. ion) m/z: 477.1 [M+H]t 27 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(2-(cyclopropylmethyl)-1-oxo-1,2,3,4-28 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 38e 29 [00379] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(cyclopropylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 38d (0.72 g, 1.91 mmol) in acetic acid (10 mL) was slowly added a solution of sodium nitrite (0.20 g, 31 2.87 mmol) in water (0.5 mL) at 0 C. The mixture was reacted for 20 minutes, N-cyanoacetylurethane (0.34 g, 2.10 32 mmol) was added, and the reaction was continued at 0 C for 4.5 hours.
Water (10 mL) was added to the reaction 33 solution. The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with 34 saturated sodium chloride (15 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a yellow solid 38e (0.97 g, yield 93%).
CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(cyclopropylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-2 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 3 [00380] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(cyclopropylmethyl)-1-oxo-1,2,3,4-4 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 38e (0.97 g, 1.78 mmol) in N,N-dimethylformamide (12 mL) was added sodium acetate (0.44 g, 5.33 mmol), and the mixture was reacted at 120 C
6 for 12 hours. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture 7 was extracted with ethyl acetate (20 mL X 3). The combined organic layers were washed with saturated sodium 8 chloride solution (20 mL X 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 9 resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1), and the obtained solid was recrystallized (petroleum ether/ethyl acetate = 3/1, 20 mL) to obtain a white solid 38 (0.13 g, 11 yield 14%, HPLC purity: 96.32%).
12 MS (ESL, neg. ion) m/z: 496.1 [M-H].
13 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 7.92-7.80 (m, 3H), 6.88-6.79 (m, 2H), 3.61 (t, J= 6.5 14 Hz, 2H), 3.45 (dt, J= 13.9, 7.1 Hz, 111), 3.35 (d, J= 6.8 Hz, 2H), 2.97 (t, J= 6.4 Hz, 211), 0.45 (q, J= 5.2 Hz, 2H), 0.26 (q, J= 4.7 Hz, 2H).
16 Example 39 2-(3,5-dichloro-44(2-(hydroxymethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-earbonitrile 39 CI CI

.fõ N o NH
CI N NH HON

19 [00381] To a solution of 2-(3,5-dichloro-441-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 1 (0.20 g, 0.45 mmol) in N-methylpyrrolidone (2 mL) were 21 added 37% formaldehyde (0.67 mL, 9.1 mmol) and ethyl phosphate. The mixture was reacted at 100 C for 24 hours.
22 The reaction solution was cooled to room temperature, and water (10 mL) was added. The mixture was extracted 23 with ethyl acetate (15 mL x 3). The combined organic layers were washed with saturated sodium chloride (15 mL
24 x 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give a white solid 39 (0.12 g, yield 56%, HPLC
26 purity: 98.48%).
27 MS (ESL, neg. ion) m/z: 472.1 [M-H];
28 'H NMR (400 MHz, DM50-d6) 8 (ppm) 13.30 (s, 111), 7.90 (d, J= 8.5 Hz, 111), 7.84 (s, 211), 6.91-6.79 (m, 29 2H), 5.87 (s, 1H), 4.87 (s, 2H), 3.57 (t, J= 6.1 Hz, 2H), 2.96 (t, J=
5.9 Hz, 2H).
Example 40 2-(3,5-diehloro-44(2-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-31 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 40 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 ci ci HN CCN
Stop 1 F
CINO2 CI NO2 Stop 2 NCINH2 Stop 3 0 lb 040a 40b CI

140 N 1.1 CI NH C Step 4 F = N 0 /41 NH step 5 F =

N-KNH

gl L'ILNHCOOEt 40c CN 404 CN 40e COOH
CI
teeeeY

101 , Step 6 F N CI N NH

2 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzy1)-3,4-dihydroisoquinolin-3 1(211)-one 40a 4 [00382] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(211)-one lb (2.0 g, 5.7 mmol) in THF (20 mL) was added sodium hydride (0.60 g, 15.0 mmol, 60 mass% in oil) at 0 C. After 10 minutes 6 of reaction, 2-bromomethy1-4-fluoro-l-methylbenzene (1.0 mL, 7.2 mmol) and N,N-dimethylformamide (2 mL) 7 were added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction was quenched 8 with water (100 mL). The mixture was extracted with ethyl acetate (120 mL). The combined organic layers were 9 washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to 11 give a white solid 40a (2.1 g, yield 77%).
12 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzy1)-3,4-dihydroisoquinolin-13 1(211)-one 40b 14 [00383] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(5-fluoro-2-methylbenzy1)-3,4-dihydroisoquinolin-1(21-1)-one 40a (2.0 g, 4.2 mmol) in acetic acid (25 mL) was added iron powder (0.60 g, 10.0 16 mmol), and the mixture was reacted at 60 C for 6 hours. The reaction solution was cooled to room temperature, 17 then water (100 mL) was added to quench the reaction. The reaction mixture was stirred for 10 minutes, filtered, 18 and rinsed with water (50 mL). The filter cake was collected and dried, and the obtained solid was slurried with 19 petroleum ether/ethyl acetate (6/1, 20 mL) to give a white solid 40b (1.1 g, yield 59%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((2-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 40c 22 [00384] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(5-fluoro-2-methylbenzy1)-3,4-23 dihydroisoquinolin-1(211)-one 40b (1.0 g, 2.2 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite 24 (0.31 g, 4.5 mmol) in water (5 mL) at 0 C, then N-cyanoacetylurethane (0.50 g, 3.0 mmol) was added. The mixture was reacted for 2 hours. Water (30 mL) was added to quench the reaction. The reaction mixture was stirred for 10 26 minutes, filtered, and rinsed with water (5 mL X 2). The filter cake was collected and dried, and the obtained solid 27 was slurried with petroleum ether/ethyl acetate (5/2, 35 mL) to give a yellow solid 40c (1.1 g, yield 80%).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-2 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 40d 3 [00385] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-4 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 40c (1.1 g, 1.8 mmol) in N,N-dimethylformamide (10 mL) was added sodium acetate (0.20 g, 2.4 mmol), and the mixture was reacted at 120 C
6 for 6 hours. The reaction solution was cooled to room temperature, then water (25 mL) was added to quench the 7 reaction. The reaction mixture was stirred for 10 minutes, and filtered.
The filter cake was collected and dried, 8 recrystallized (ethanol/ethyl acetate/petroleum ether = 5/14/20, 39 mL) at 80 C to obtain a white solid 40d (0.66 g, 9 yield 65%, HPLC purity: 97.55%).
MS (ESL, neg. ion) m/z: 564.0 [M-1-1]-;
11 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.34 (s, 1H), 7.93 (d, J= 8.2 Hz, 1H), 7.85 (s, 2H), 7.30-7.15 (m, 12 1H), 6.98 (dd, J= 17.3, 5.6 Hz, 2H), 6.86 (d, J= 9.5 Hz, 2H), 4.67 (s, 2H), 3.50-3.44 (m, 2H), 2.99 (s, 211), 2.25 (s, 13 3H).
14 Step 5: Synthesis of 2-(3,5-dichloro-44(245-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 40e 16 [00386] 2-(3,5-Dichloro-442-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 40d (0.60 g, 1.1 mmol) was dissolved in 18 acetic acid (10 mL), then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 120 C for 19 12 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and 21 dried to obtain a yellow solid 40e (0.40 g, yield 60%).
22 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-23 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 40 24 [00387] 2-(3,5-Dichloro-442-(5-fluoro-2-methylbenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 40e (0.40 g, 0.68 mmol) was 26 dissolved in thioglycolic acid (3 mL). The mixture was reacted at 150 C
for 12 hours. The reaction solution was 27 cooled to room temperature, and ethyl acetate (50 mL) was added. The mixture was washed successively with water 28 (10 mL) and saturated sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated 29 by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1), and the obtained solid was recrystallized at 80 C (ethyl acetate/petroleum ether = 1/2, 24 mL) to give a white 31 solid 40 (0.29 g, yield 78%, HPLC purity: 99.21%).
32 MS (ESL, neg. ion) m/z: 539.2 [M-H]-;
33 IHNMR (400 MHz, DMSO-d6) 8(ppm) 12.52 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 111), 7.23 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 (dd, J= 8.3, 6.0 Hz, 1H), 7.03-6.93 (m, 2H), 6.86-6.80 (m, 2H), 4.67 (s, 2H), 3.49 (t, J= 6.6 Hz, 2H), 2.99 (t, J=
2 6.6 Hz, 2H), 2.25 (s, 311).
3 Example 41 2-(3,5-dichloro-441-oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-4 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 41 o HN RIP
CI NO2 F3C0 0 ilk, Step 1 51111r _____________________________________________________ Step 2 101 N

Step 3 lb 41 0 41b CI CI
CI
F300 is is 0L F3C0 io F3con, -11 .tiNH 0 Step 4 N CI NH
step 5 -"N CI - N NH
'rjl'NHCOOEt 0 0 N
41c CN 41d CN
41e COOH
Cl F3C0 rii..ThrThõ.0 3 Step CI N NH
o 41 6 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzy1)-3,4-dihydroisoquinolin-7 1(2H)-one 41a 8 [00388] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (1.50 g, 4.20 9 mmol) in N,N-dimethylformamide (6 mL) and THF (20 mL) was added sodium hydride (0.25 g, 6.25 mmol, 60 mass% in oil) at 0 C. After 30 minutes of reaction, 4-trifluoromethoxybenzyl bromide (2.27 g, 8.90 mmol) was 11 added dropwise, and the mixture was reacted at room temperature for 3 hours. The reaction was quenched with ice 12 water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 2), dried over anhydrous sodium sulfate and 13 concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 14 ether/ethyl acetate = 4/1) to give yellow oil 41a (2.07 g, yield 93%).
MS (ESL pos. ion) m/z: 527.00 [M+H]t 16 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzy1)-3,4-17 dihydroisoquinolin-1(2H)-one 41b 18 [00389] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(4-(trifluoromethoxy)benzy1)-3,4-19 dihydroisoquinolin-1(211)-one 41a (2.07 g, 3.93 mmol) in acetic acid (50 mL) was added iron powder (0.88 g, 15.7 mmol), and the mixture was reacted at 55 C for 5 hours. The reaction solution was cooled to room temperature. The 21 reaction was quenched with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined 22 organic layers were washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate and 23 concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 24 ether/ethyl acetate = 5/1) to give a white solid 41b (1.59 g, yield 81%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((l-oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 41c 2 [00390] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(4-(trifluoromethoxy)benzy1)-3,4-3 dihydroisoquinolin-1(211)-one 41b (0.60 g, 1.21 mmol) in acetic acid (12 mL) was added a solution of sodium nitrite 4 (0.17 g, 2.48 mmol) in water (6 mL) at 0 C, then N-cyanoacetylurethane (0.23 g, 1.49 mmol) was added. The mixture was reacted for 4 hours. Water (100 mL) was added to quench the reaction. The mixture was stirred for 30 6 minutes, filtered, and the filter cake was washed with water (10 mL x 2).
Then the filter cake was collected and 7 dried to obtain a yellow solid 41c (0.87 g, yield 100%).
8 Step 4: Synthesis of 2-(3,5-dichloro-44(1-oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-9 6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,24-triazine-6-carbonitrile 41d [00391] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-41-oxo-2-(4-(trifluoromethoxy)benzy1)-11 1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 41c (0.87 g, 1.21 mmol) in N,N-12 dimethylformamide (18 mL) was added sodium acetate (0.22 g, 2.65 mmol), and the mixture was reacted at 120 C
13 for 6 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added to quench the 14 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, recrystallized (ethanol/ethyl acetate/petroleum ether = 1/1/4, 30 mL) at 80 C
to obtain a light red solid 41d (0.65 g, 16 yield 88%, HPLC purity: 98.61%).
17 MS (ESL neg. ion) m/z: 616.0 [M-H]-;
18 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 114), 7.93 (d, J= 8.4 Hz, 1H), 7.84(s, 211), 7.44 (d, J = 8.2 19 Hz, 2H), 7.33 (d, J= 8.2 Hz, 2H), 6.85 (d, J= 10.7 Hz, 2H), 4.72 (s, 2H), 3.51 (t, J= 6.3 Hz, 2H), 2.98 (t, J = 6.1 Hz, 2H).
21 Step 5: Synthesis of 2-(3,5-dichloro-4-((2-(1-oxo-4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-22 6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 41e 23 [00392] 2-(3,5 -Dichloro-4-((1 -oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-24 yfloxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 41d (0.32 g, 0.52 mmol) was dissolved in acetic acid (10 mL), then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 26 11 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction 27 mixture was stirred for 10 minutes, filtered, and rinsed with water (5 mL x 2). The filter cake was collected and 28 dried to obtain a yellow solid 41e (0.35 g, yield 100%).
29 Step 6: 2-(3,5-dichloro-4-((l-oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 41 31 [00393] 2-(3,5 -Dichloro-4-((1 -oxo-2-(4-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-32 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 41e (0.35 g, 0.53 mmol) was 33 dissolved in thioglycolic acid (3 mL). The mixture was reacted at 140 C
for 14 hours. The reaction solution was 34 cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 (10 mL) and saturated sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated 2 by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 3 =
3/1), and the obtained solid was recrystallized at 85 C (ethyl acetate/petroleum ether = 1/1, 20 mL) to give a white 4 solid 41 (0.22 g, yield 71%, HPLC purity: 99.21%).
MS (ESL, neg. ion) m/z: 591.0 [M-1-1]-;

111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.52 (s, 1H), 7.93 (d, J= 8.4 Hz, 1H), 7.87 (s, 2H), 7.73 (s, 1H), 7.44 (d, J= 8.3 Hz, 2H), 7.33 (d, J= 8.2 Hz, 2H), 6.87-6.78 (m, 2H), 4.72 (s, 2H), 3.51 (t, J= 6.6 Hz, 2H), 2.97 (t, 8 J= 6.6 Hz, 2H).
9 Example 42 2-(3,5-dichloro-4-02-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ylloxylpheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-earbonitrile 42 a o,, o r N I .õ,.
F =

F alit, N I
HN -"- ______________________ F 0 N
Step , 0 Step 2 Step 3 '- CI NO2 Step 4 5a 42a 42b 42c CI
CI CI

Ob, / A
i stet, 5 F
N CI NH2 N I ....- ).--- N
. ....... SteP6 CI Ir\li,,,'7)1' 0 ' F N I
42d 42e 42f ON
CI CI

I
I, 0 Step 7 F ith N
CI 4111111" NANH Step 8 F 0 N
õ...,.
CI flN1H
11 42g COOH 42 12 Step 1: Synthesis of 2-(3-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 42a [00394] 6-Methoxy-3,4-dihydroisoquinolin-1(211)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), m-fluoroiodobenzene (3.76 g, 16.9 mmol) and potassium carbonate (1.17 g, 8.47 mmol) were dissolved in N,N-dimethylformamide (40 mL), and the mixture was reacted at 150 C for 19 hours. The reaction solution was cooled to room temperature, then water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL X 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a yellow solid 42a (2.22 g, yield 96%).
19 MS (ESL, pos. ion) m/z: 272.2 [M+H]t Step 2: Synthesis of 2-(3-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(21-1)-one 42b [00395] At 0 C, to a solution of 2-(3-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 42a (2.22 22 g, 8.17 mmol) in dichloromethane (30 mL) was added boron tribromide (2.4 mL, 25.0 mmol) dropwise. Then the mixture was reacted at room temperature for 4 hours. The reaction solution was quenched by pouring into ice water (30 mL). The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried, and the obtained solid was purified by silica gel column chromatography (petroleum CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 ether/ethyl acetate = 3/1) to obtain a white solid 42b (0.13 g, yield 4.5%).
2 MS (ESL pos. ion) m/z: 258.1 [M+H]t 3 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 4 42c [00396] To a solution of 2-(3-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 42b (0.13 g, 0.51 6 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.13 g, 0.57 mmol) in NN-dimethylformamide (3 mL) was added 7 potassium carbonate (0.14 g, 1.01 mmol), and the mixture was reacted at 70 C for 2 hours. The reaction solution 8 was cooled to room temperature, then water (10 mL) was added. The reaction mixture was stirred for 10 minutes, 9 filtered, and rinsed with water (5 mL). The filter cake was collected and dried to obtain an off-white solid 42c (0.22 g, yield 97%).
11 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 12 42d 13 [00397] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-14 one 42c (0.22 g, 0.49 mmol) in acetic acid (6 mL) was added iron powder (0.11 g, 1.95 mmol), and the mixture was reacted at 55 C for 6 hours. The reaction solution was cooled to room temperature, iron powder was removed, and 16 water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers 17 were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated 18 by suction filtration to give a white solid 42d (0.18 g, yield 85%).
19 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 42e 21 [00398] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-fluoropheny1)-3,4-dihydroisoquinolin-22 1(211)-one 42d (0.18 g, 0.42 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (58 mg, 0.84 23 mmol) in water (5 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (79 mg, 0.51 mmol) 24 was added, and the mixture was reacted for 3.5 hours. Water (20 mL) was added to the reaction solution. The mixture was stirred for 10 minutes, filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain 26 a yellow solid 42e (0.19 g, yield 73%).
27 Step 6: Synthesis of 2-(3,5-dichloro-44(2-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-28 yl)oxy)pheny1)-3,5 -dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 42f 29 [00399] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 42e (0.35 g, 0.60 mmol) in N,N-31 dimethylformamide (40 mL) was added sodium acetate (0.12 g, 1.40 mmol), and the mixture was reacted at 120 C
32 for 8 hours. The reaction solution was cooled to room temperature, and water (80 mL) was added to quench the 33 reaction. The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic layers were washed 34 with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate), and the CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 obtained solid was recrystallized (petroleum ether/ethyl acetate = 1/2, 24 mL) at 80 C to obtain a yellow solid 42f 2 (0.25 g, yield 76%, HPLC purity: 99.44%).
3 MS (ESL neg. ion) m/z: 536.1 [M-1-1]-;
4 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 1H), 7.96 (d, J= 8.7 Hz, 1H), 7.86(s, 2H), 7.45 (q, J= 7.8 Hz, 1H), 7.34-7.23 (m, 2H), 7.09 (td, J= 8.6, 2.6 Hz, 1H), 6.95 (d, J= 2.6 Hz, 1H), 6.89 (dd, J= 8.7, 2.6 Hz, 1H), 6 3.97 (t, J= 6.4 Hz, 2H), 3.13 (t, J= 6.4 Hz, 2H).
7 Step 7: Synthesis of 2-(3,5-dichloro-4-42-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-8 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 42g 9 [00400] 2-(3,5-Dichloro-442-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 42f (0.26 g, 0.49 mmol) was dissolved in acetic acid (5 mL), 11 then concentrated hydrochloric acid (2.5 mL) was added. The mixture was reacted at 100 C for 7 hours. The reaction 12 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 13 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 14 42g (0.22 g, yield 78%).
Step 8: Synthesis of 2-(3,5-dichloro-44(2-(3-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-16 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 42 17 [00401] 2-(3,5-Dichloro-44(2-(3-fl uoroph eny1)-1-oxo-1,2,3,4-tetrahydroi soqui nol in-6-yl)oxy)pheny1)-3,5-18 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 42g (0.22 g, 0.40 mmol) was dissolved in thioglycolic 19 acid (2 mL). The mixture was reacted at 140 C for 14 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated 21 sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated by suction filtration.
22 The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), and the 23 obtained solid was recrystallized at 85 C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give a white solid 42 (88 24 mg, yield 43%, HPLC purity: 98.94%).
MS (ESL, neg. ion) m/z: 511.1 [M-11]-;
26 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 12.53 (s, 1H), 7.96 (s, 1H), 7.88 (s, 2H), 7.74 (s, 1H), 7.45 (s, 1H), 27 7.28 (dd, J= 21.9, 9.6 Hz, 21-1), 7.10 (s, 1H), 6.93 (s, 11-1), 6.86 (s, 1H), 3.97 (s, 2H), 3.13 (s, 2H).
28 Example 43 2-(3,5-dichloro-4-(0-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-29 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 43 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 CI ocF, CI OCF3 CI

HN RI=461, P CI NO2 SLp 1 141 SLop 2 Ng10:-,o SLep 3 CljalLNO2 CI-jacH2 lb 43a 43b = 0 N 101 4-(C- JL ____ 140 SL
NH
0 Step 4 01 NH Stop 5 01 N NH
0 NI-,11'NHCOOEt 0 NL0 0 43c ON 43d CN 43e COOH

Stop 6 0 1401 ,N NANH

2 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzyl)-3,4-dihydroisoquinolin-3 1(211)-one 43a 4 [00402] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(211)-one lb (2.5 g, 7.1 mmol) in THF (25 mL) was added sodium hydride (0.60 g, 20 mmol, 60 mass% in oil) at 0 C. Then 3-6 trifluoromethoxybenzyl bromide (1.4 g, 8.6 mmol) and N,N-dimethylformamide (2 mL) were added dropwise and 7 the mixture was reacted at 0 C for 5 hours. The reaction was quenched with water (100 mL). The mixture was 8 extracted with ethyl acetate (200 mL). The combined organic layers were washed with saturated sodium chloride 9 (30 mL X 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give yellow oil 43a (2.6 g, yield 70%).
11 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzy1)-3,4-12 dihydroisoquinolin-1(211)-one 43b 13 [00403] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(3-(trifluoromethoxy)benzy1)-3,4-14 dihydroisoquinolin-1(211)-one 43a (2.5 g, 4.7 mmol) in acetic acid (30 mL) was added iron powder (0.55 g, 9.8 mmol), and the mixture was reacted at 60 C for 6 hours. The reaction solution was cooled to room temperature. The 16 reaction was quenched with water (60 mL). The mixture was extracted with ethyl acetate (150 mL). The combined 17 organic layers were washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate and 18 concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 19 ether/ethyl acetate = 4/1) to give yellow oil 43b (1.5 g, yield 64%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-44(1-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-21 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 43c 22 [00404] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(3-(trifluoromethoxy)benzy1)-3,4-23 dihydroisoquinolin-1(211)-one 43b (1.5 g, 3.0 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite 24 (0.42 g, 6.1 mmol) in water (6 mL) at 0 C, then N-cyanoacetylurethane (0.61 g, 3.9 mmol) was added. The mixture was reacted for 2 hours. Water (30 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, 26 filtered, and the filter cake was washed with water (10 mL x 2). Then the filter cake was collected and dried to 27 obtain a yellow solid 43c (1.6 g, yield 80%).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 Step 4: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-2 6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 43d 3 [00405] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-41-oxo-2-(3-(trifluoromethoxy)benzy1)-4 1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 43c (1.5 g, 3.7 mmol) in N,N-dimethylformamide (15 mL) was added sodium acetate (0.30 g, 3.7 mmol), and the mixture was reacted at 120 C
6 for 6 hours. The reaction solution was cooled to room temperature, then water (35 mL) was added to quench the 7 reaction. The reaction mixture was stirred for 10 minutes, and filtered.
The filter cake was collected and dried, 8 recrystallized (ethanol/ethyl acetate/petroleum ether = 5/20/18, 43 mL) at 85 C to obtain a white solid 43d (0.80 g, 9 yield 57%, HPLC purity: 98.83%).
MS (ESL, neg. ion) m/z: 616.0 [M-H];
11 111 NMR (400 MHz, DMSO-d6) 5 (ppm) 13.33 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.84 (s, 2H), 7.48 (t, J= 7.8 12 Hz, 1H), 7.36 (d, J= 7.7 Hz, 1H), 7.33-7.13 (m, 2H), 6.85 (d, J= 9.3 Hz, 2H), 4.74 (s, 2H), 3.52 (t, J= 6.4 Hz, 2H), 13 2.97 (t, J= 6.2 Hz, 2H).
14 Step 5: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-yl)ox y)pheny1)-3,5 -di oxo-2,3,4,5-tetrahydro-1,2,4-triazin e-6-carboxyl ic acid 43e 16 [00406] 2-(3,5-Dichloro-4-((l-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-17 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1 ,2,4-triazine-6-carbonitrile 43d (0.80 g, 1.3 mmol) was dissolved in 18 acetic acid (12 mL), then concentrated hydrochloric acid (4 mL) was added. The mixture was reacted at 120 C for 19 12 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (5 mL x 2). The filter cake was collected and 21 dried to obtain a white solid 43e (0.62 g, yield 75%).
22 Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-23 6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 43 24 [00407] 2-(3,5-Dichloro-4-((l-oxo-2-(3-(trifluoromethoxy)benzy1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 43e (0.62 g, 0.97 mmol) was 26 dissolved in thioglycolic acid (3.5 mL). The mixture was reacted at 150 C for 12 hours. The reaction solution was 27 cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was extracted with 28 ethyl acetate (60 mL >< 2). The combined organic layers were washed with saturated sodium chloride solution (15 29 mL x 3), dried over anhydrous sodium sulfate and concentrated by suction filtration. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate =
1/3), and the obtained solid was 31 recrystallized at 85 C (ethyl acetate/petroleum ether = 2/5, 21 mL) to give a white solid 43 (0.38 g, yield 66%, 32 purity: 98.38%).
33 MS (ESL, neg. ion) m/z: 591.1 [M-11]-;
34 11-1 NMR (400 MHz, DMSO-d6) 5 (ppm) 12.52 (s, 1H), 7.93 (d, J= 8.3 Hz, 1H), 7.87 (d, J= 1.0 Hz, 2H), 7.73 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 (d, J= 1.4 Hz, 1H), 7.48 (t, J= 7.9 Hz, 1H), 7.35 (d, J= 7.7 Hz, 1H), 7.32-7.15 (m, 2H), 6.96-6.64 (m, 2H), 4.74 2 (s, 211), 3.51 (t, J= 6.6 Hz, 2H), 2.97 (t, J= 6.6 Hz, 2H).
3 Example 44 2-(3,5-dichloro-442-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-4 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41/)-dione 44 a C:o. F 10 F OH
0 1,1 F
_______________________________________________________________________________ _____ , HN I N
Step 1 1W. 71 Step 2 lei N Step 3 a ..., N CI NO2 Step 4 0 0 1 ...." 0 5a 44a 44b 44c CI
GI GI

F 0 0 __ . N W
CIN JLNH
N 40 0 Step 5 dia.t.F N so N_Nyi,N10,,,,,,, Step 6 -- 0110 ) j / 0 I. 0 H
CN

44d 44e 44f CN
CI CI

.... F 6 1 F aii 1 Step _____________ 7 so N
CI 411111.rr N NH Step 8 so NCI 'Il.
N NH
0 N rLc) 0 N o 44g COOH 44 6 Step 1: Synthesis of 2-(2-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 44a [00408] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), o-fluoroiodobenzene (3.76 g, 16.9 mmol) and potassium carbonate (1.17 g, 8.47 mmol) were dissolved in N,N-dimethylformamide (40 mL), and the mixture was reacted at 150 C for 19 hours. The reaction solution was cooled to room temperature, then water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL X 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a yellow solid 44a (1.76 g, yield 75%).
13 MS (ESL pos. ion) m/z: 272.2 [M+H]t 14 Step 2: Synthesis of 2-(2-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(211)-one 44b [00409] At 0 C, to a solution of 2-(2-fluoropheny1)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one 44a (1.72 16 g, 6.34 mmol) in dichloromethane (30 mL) was added boron tribromide (1.84 mL, 19.1 mmol) dropwise. Then the mixture was reacted at room temperature for 4 hours. The reaction solution was quenched by pouring into ice water (30 mL). The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried, and the obtained solid was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain a white solid 44b (1.09 g, yield 67%).
21 MS (ESL pos. ion) m/z: 258.2 [M+H]t 22 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 23 44c [00410] To a solution of 2-(2-fluoropheny1)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 44b (0.50 g, 1.94 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.52 g, 2.28 mmol) in NN-dimethylformamide (3 mL) was added CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 potassium carbonate (0.54 g, 3.89 mmol), and the mixture was reacted at 40 C for 4.5 hours. The reaction solution 2 was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, 3 filtered, and rinsed with water (5 mL). The filter cake was collected and dried to obtain an off-white solid 44c (0.92 4 g, yield 100%).
Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-one 6 44d 7 [00411] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(2-fluoropheny1)-3,4-dihydroisoquinolin-1(2H)-8 one 44c (0.92 g, 2.06 mmol) in acetic acid (10 mL) was added iron powder (0.46 g, 8.24 mmol), and the mixture 9 was reacted at 55 C for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL >< 2). The combined organic 11 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and 12 concentrated by suction filtration to give a white solid 44d (0.84 g, yield 98%).
13 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichl oro-442-(2-fluoroph eny1)-1-oxo-1,2,3,4-14 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 44e [00412] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(2-fluoropheny1)-3,4-dihydroisoquinolin-16 1(211)-one 44d (0.55 g, 1.32 mmol) in acetic acid (11 mL) was added a solution of sodium nitrite (0.18 g, 2.64 17 mmol) in water (6 mL) dropwise at 0 C. After reacting for 15 minutes, N-cyanoacetylurethane (0.25 g, 1.58 mmol) 18 was added, and the mixture was reacted for 3.5 hours. Water (20 mL) was added to the reaction solution. The mixture 19 was stirred for 10 minutes, filtered, washed with water (10 mL), and the filter cake was collected and dried to obtain a yellow solid 44e (0.76 g, yield 99%).
21 Step 6: Synthesis of 2-(3,5-dichloro-4-42-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-22 yl)oxy)pheny1)-3,5 -dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 44f 23 [00413] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(2-fluoropheny1)-1-oxo-1,2,3,4-24 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 44e (0.42 g, 0.72 mmol) in N,N-dimethylformamide (10 mL) was added sodium acetate (0.13 g, 1.59 mmol), and the mixture was reacted at 120 C
26 for 8 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added to quench the 27 reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake 28 was collected and dried, and the obtained solid was recrystallized at 80 C (petroleum ether/ethyl acetate = 1/2, 30 29 mL) to give a yellow solid 44f (0.25 g, yield 65%, HPLC purity: 96.68%).
MS (ESL neg. ion) m/z: 536.0 [M-1-1]-;
31 11-1 NMR (400 MHz, DMSO-d6) 5 (ppm) 13.31 (s, 1H), 7.95 (d, J= 8.5 Hz, 111), 7.86 (s, 2H), 7.48 (t, J= 7.7 32 Hz, 1H), 7.42-7.35 (m, 1H), 7.33 (d, J= 10.7 Hz, 1H), 7.28 (d, J= 8.2 Hz, 1H), 6.97 (s, 1H), 6.89 (d, J= 8.7 Hz, 33 1H), 3.93-3.83 (m, 2H), 3.20-3.11 (m, 2H).
34 Step 7: Synthesis of 2-(3,5-dichloro-44(2-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 44g 2 [00414] 2-(3,5-Dichloro-442-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-3 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 44f (0.55 g, 1.02 mmol) was dissolved in acetic acid (10 mL), 4 then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 7 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred for 10 6 minutes, filtered, and rinsed with water (10 mL X 2). The filter cake was collected and dried to obtain a yellow solid 7 44g (0.56 g, yield 98%).
8 Step 8: Synthesis of 2-(3,5-dichloro-44(2-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-9 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 44 [00415] 2-(3,5-Dichloro-44(2-(2-fluoropheny1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)pheny1)-3,5-11 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 44g (0.56 g, 1.01 mmol) was dissolved in thioglycolic 12 acid (2 mL). The mixture was reacted at 130 C for 14 hours. The reaction solution was cooled to room temperature, 13 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated 14 sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), and the obtained 16 solid was recrystallized at 85 C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give a white solid 44 (0.23 g, yield 17 44%, HPLC purity: 97.70%).
18 MS (ESL neg. ion) m/z: 511.0 [M-1-1]-;
19 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.53 (s, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.89 (s, 2H), 7.74 (s, 1H), 7.48 (td, J= 7.8, 1.8 Hz, 1H), 7.41-7.25 (m, 3H), 6.95 (d, J= 2.6 Hz, 1H), 6.86 (dd, J= 8.6, 2.6 Hz, 1H), 3.88 (t, J
21 = 6.4 Hz, 2H), 3.14 (t, J= 6.5 Hz, 2H).
22 Example 45 2-(3,5-dichloro-441-oxo-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-23 ylloxylpheny1)-1,2,4-triazine-3,5(2H,411)-dione 45 41.11, HN CINO, Step 1 Nra...,./rJe = 3, Step 2 N N
Step 3 CI

lb 46a 46b CI CI
CI
0,2, u, r = j;
CV o.,, - - NH 0 Step N N No.,õ
N -1,1H
step 5 CI N't 'NH
0 il,"j 0 -L
NHCOOEt y 46c CN 46d CN
46e COOH

o Step 6 N-C1 41111frP NNH

Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 one 45a 2 [00416] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(21/)-one lb (2.0 g, 5.7 3 mmol) in THF (20 mL) was added sodium hydride (0.70 g, 18 mmol, 60 mass%
in oil) at 0 C. Then 3-4 (bromomethyl)pyridine hydrobromide (1.9 g, 7.5 mmol) and N,N-dimethylformamide (6 mL) were added, and the mixture was reacted at 20 C for 4 hours. Water (50 mL) was added to quench the reaction at 0 C. The mixture was 6 stirred for 10 minutes, and filtered. The filter cake was rinsed with water (20 mL x 3), and the collected filter cake 7 was dried and slurried with ethyl acetate/petroleum ether (1/2, 20 mL).
The mixture was filtered, and the filter cake 8 was collected and dried to obtain a yellow solid 45a (2.2 g, yield 87%).
9 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one 45b 11 [00417] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-12 1(210-one 45a (2.2 g, 5.0 mmol) in acetic acid (25 mL) was added iron powder (0.72 g, 13 mmol), and the mixture 13 was reacted at 60 C for 6 hours. The reaction solution was cooled to room temperature, then water (100 mL) was 14 added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate, and 16 concentrated by suction filtration to give a yellow solid 45b (1.6 g, yield 78%).
17 Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-18 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 45c 19 [00418] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-3-ylmethyl)-3,4-dihydroisoquinolin-1(211)-one 45b (1.6 g, 3.9 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.35 g, 5.1 mmol) 21 in water (5 mL) at 0 C, then N-cyanoacetylurethane (0.72 g, 4.6 mmol) was added. The mixture was reacted for 2 22 hours. Water (100 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, and the 23 filter cake was collected and dried to obtain a yellow solid 45c (2.2 g, yield 98%).
24 Step 4: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 45d 26 [00419] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-27 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 45c (2.2 g, 3.8 mmol) in N,N-28 dimethylformamide (18 mL) was added sodium acetate (0.40 g, 4.9 mmol), and the mixture was reacted at 120 C
29 for 6 hours. The reaction solution was cooled to room temperature, then water (100 mL) was added to quench the reaction. The reaction mixture was stirred for 15 minutes, and filtered. The filter cake was collected and dried, then 31 slurried with ethanol/ethyl acetate (1/3, 50 mL) at 85 C to give a white solid 45d (0.90 g, yield 40%, HPLC purity:
32 83.86%).
33 MS (ESL, pos. ion) m/z: 535.9 [M+Hr;
34 1HNMR (400 MHz, DMSO-d6) 8 (ppm) 8.56 (d, J= 28.8 Hz, 2H), 8.05-7.68 (m, 4H), 7.49-7.35 (m, 1H), 6.83 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 (d, J= 9.2 Hz, 2H), 4.71 (s, 2H), 3.52 (d, J= 6.7 Hz, 2H), 2.96 (t, J=
6.6 Hz, 2H).
2 Step 5: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-3 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 45e 4 [00420] 2-(3,5-Dichloro-4((2-(pyridin-3-ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 45d (0.80 g, 1.5 mmol) was dissolved in acetic acid (12 6 mL), then concentrated hydrochloric acid (6.0 mL) was added. The mixture was reacted at 120 C for 12 hours. The 7 reaction solution was cooled to room temperature, and concentrated in vacuo to obtain a yellow solid 45e (0.80 g, 8 yield 97%).
9 Step 6: Synthesis of 2-(3,5-dichloro-4-((2-(pyridin-3-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 45 11 [00421] 2-(3,5-Dichloro-4((2-(pyridin-3-ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-12 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 45e (0.80 g, 1.4 mmol) was dissolved in thioglycolic 13 acid (2 mL). The mixture was reacted at 140 C for 12 hours. The reaction solution was cooled to room temperature 14 and the reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to obtain a white solid 45 (0.12 g, yield 20%, HPLC purity: 93.09%).
16 MS (ESL, neg. ion) m/z: 511.0 [M+H];
17 'H NMR (400 MHz, DMSO-d6) 8 (ppm) 12.53 (s, 1H), 9.08-8.68 (m, 2H), 8.41 (d, J= 12.8 Hz, 1H), 8.14-7.80 18 (m, 411), 7.74 (d, J= 1.8 Hz, 1H), 7.05-6.70 (m, 2H), 4.84 (d, J= 2.9 Hz, 2H), 3.62 (d, J= 6.8 Hz, 211), 3.02 (t, J=
19 6.6 Hz, 2H).
Example 46 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-21 yl)oxylpheny1)-1,2,4-triazine-3,5(2H,41/)-dione 46 ati o Step ft, H N
Step 3 NO2 __ 1 'N N __ 111111111-1-1P CI 4111111." NO, Step 2 N
CI = NH2 0 0 lb 46a 046b CI CI
CI
0, 0, 0 0,11) 0 ji 1101 jt,), A :LN
CI' NH 0 Step 4 N CI N H step 5 N CK-LL'--AN-jj'NH

N HCOOEt 0 46c CN 46d CN 46e COOH
CI

Step ______________ 6 N CI N NH

23 Step 1: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-24 one 46a [00422] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-3,4-dihydroisoquinolin-1(2H)-one lb (2.0 g, 5.7 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 mmol) in THF (20 mL) was added sodium hydride (0.60 g, 15 mmol, 60 mass%
in oil) at 0 C. Then 3-2 (bromomethyl)pyridine hydrobromide (1.9 g, 7.5 mmol) and N,N-dimethylformamide (2 mL) were added, and the 3 mixture was reacted at 15 C for 6 hours. The reaction was quenched by adding water (50 mL) at 0 C. The mixture 4 was stirred for 10 minutes, extracted with ethyl acetate (120 mL). The combined organic layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration 6 to give a yellow solid 46a (2.3 g, 91% yield).
7 Step 2: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-8 one 46b 9 [00423] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-1(211)-one 46a (2.3 g, 5.2 mmol) in acetic acid (25 mL) was added iron powder (0.72 g, 13 mmol), and the mixture 11 was reacted at 60 C for 6 hours. The reaction solution was cooled to room temperature, then water (80 mL) was 12 added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic 13 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and 14 concentrated by suction filtration to give black oil 46b (2.1 g, yield 98%).
Step 3: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-16 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 46c 17 [00424] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-2-ylmethyl)-3,4-dihydroisoquinolin-18 1(211)-one 46b (2.1 g, 5.1 mmol) in acetic acid (20 mL) was added a solution of sodium nitrite (0.45 g, 6.5 mmol) 19 in water (5 mL) at 0 C, then N-cyanoacetylurethane (0.95 g, 6.1 mmol) was added. The mixture was reacted for 2 hours. Water (50 mL) was added to quench the reaction. The mixture was stirred for 10 minutes, filtered, and the 21 filter cake was collected and dried to obtain a yellow solid 46c (2.8 g, yield 95%).
22 Step 4: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-23 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbon itril e 46d 24 [00425] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-442-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 46c (2.8 g, 4.8 mmol) in N,N-26 dimethylformamide (30 mL) was added sodium acetate (0.43 g, 5.2 mmol), and the mixture was reacted at 120 C
27 for 6 hours. The reaction solution was cooled to room temperature, then water (50 mL) was added to quench the 28 reaction. The reaction mixture was stirred for 15 minutes, and filtered.
The filter cake was collected and dried, then 29 recrystallized with ethyl acetate/petroleum ether (2/1, 30 mL) at 85 C
to give a white solid 46d (1.3 g, yield 50%, HPLC purity: 91.60%).
31 MS (ESL, pos. ion) m/z: 535.9 [M+H];
32 11-1 NMR (400 MHz, DMSO-d6) 5 (ppm) 13.11 (s, 111), 8.51 (d, J= 4.8 Hz, 1H), 8.16-7.81 (m, 3H), 7.76 (t, J
33 = 7.8 Hz, 1H), 7.51-7.11 (m, 2H), 7.05- 6.72 (m, 2H), 4.78 (s, 2H), 3.61 (t, J= 6.6 Hz, 2H), 3.01 (t, J= 6.5 Hz, 2H).
34 Step 5: Synthesis of 2-(3,5-dichloro-44(2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 46e 2 [00426] 2-(3,5-Dichloro-4((2-(pyridin-2-ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 46d (1.2 g, 2.2 mmol) was dissolved in acetic acid (12 4 mL), then concentrated hydrochloric acid (6.0 mL) was added. The mixture was reacted at 120 C for 12 hours. The reaction solution was cooled to room temperature, and concentrated in vacuo to obtain a yellow solid 46e (1.2 g, 6 yield 97%).
7 Step 6: Synthesis of 2-(3,5-diehloro-44(2-(pyridin-2-ylmethyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-8 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 46 9 [00427] 2-(3,5-Dichloro-4((2-(pyridin-2-ylmethyl)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 46e (1.0 g, 1.8 mmol) was dissolved in thioglycolic 11 acid (3 mL). The mixture was reacted at 140 C for 12 hours. The reaction solution was cooled to room temperature 12 and the reaction solution was purified by silica gel column chromatography (petroleum ether/ethyl acetate=7/3) to 13 obtain a white solid 46 (0.43 g, yield 47%, HPLC purity: 92.83%).
14 MS (ESL neg. ion) m/z: 511.0 [M+H];
111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.52 (s, 111), 8.51 (d, J= 4.8 Hz, 1H), 8.02-7.83 (m, 311), 7.83-7.63 16 (m, 2H), 7.38-7.23 (m, 2H), 6.93-6.76 (m, 2H), 4.78 (s, 2H), 3.61 (t, J=
6.6 Hz, 2H), 3.01 (t, J= 6.6 Hz, 2H).
17 Example 47 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-18 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-3,5(2H,411)-dione 47 OH

N N
ge Step 1 Step 2 3 N N
Ci Step 4 5a 47a 47b 47c CI
CI CI
Ati 0 At 0 1 \ \ 0 o õN, N WI Mr NH 2 Stet' 5 N Nyt, A
Step 6 CD. N GI N NH
CI
0 CI N" N

N
-o 47d 47e 47f CN
CI CI

Step 7 'JCL
CI N NH Step 8 N NIiç1 N NH
o 0 19 47g COOH 47 Step 1: Synthesis of 6-methoxy-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 47a 21 [00428] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.48 g, 2.5 22 mmol), 2-iodopyridine (3.5 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in N,N-23 dimethylformamide (40 mL), and the mixture was reacted at 150 C for 11 hours. The reaction solution was cooled 24 to room temperature, and water (40 mL) was added to quench the reaction.
The mixture was extracted with ethyl acetate (60 mL X 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 ahydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column 2 chromatography (petroleum ether/ethyl acetate = 2/1) to give a white solid 47a (1.66 g, yield 77%).
3 MS (ESL, pos. ion) m/z: 255.1 [M+H]t 4 Step 2: Synthesis of 6-hydroxy-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 47a [00429] At 0 C, to a solution of 6-methoxy-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 47a (1.67 g, 6 6.54 mmol) in dichloromethane (40 mL) was added boron tribromide (1.60 mL, 16.6 mmol) dropwise. Then the 7 mixture was reacted at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water 8 (30 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and 9 the filter cake was collected and dried to obtain a white solid 47b (1.06 g, yield 68%).
MS (ESL, pos. ion) m/z: 258.2 [M+H]t 11 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 47c 12 [00430] To a solution of 6-hydroxy-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(21-1)-one 47b (1.06 g, 4.41 13 mmol) and 1,2,3-trichloro-5-nitrobenzene (1.10 g, 4.86 mmol) in NN-dimethylformamide (6 mL) was added 14 potassium carbonate (1.22 g, 8.83 mmol), and the mixture was reacted at 40 C for 5.5 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, 16 filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain a white solid 47c (1.75 g, 17 yield 92%).
18 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 19 47d [00431] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-21 one 47c (1.75 g, 4.07 mmol) in acetic acid (30 mL) was added iron powder (0.91 g, 16.3 mmol), and the mixture 22 was reacted at 55 C for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, 23 and water (50 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic 24 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a white solid 47d (1.45 g, yield 89%).
26 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyridin-2-y1)-1,2,3,4-27 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 47e 28 [00432] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-2-y1)-3,4-dihydroisoquinolin-1(2H)-29 one 47d (0.40 g, 1.0 mmol) in acetic acid (8 mL) was added a solution of sodium nitrite (0.14 g, 2.0 mmol) in water (4 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (0.16 g, 1.0 mmol) was added, and 31 the mixture was reacted for 3 hours. Water (20 mL) was added to the reaction solution. The mixture was stirred for 32 10 minutes, filtered, washed with water (10 mL x 2), and the filter cake was collected and dried to obtain a yellow 33 solid 47e (0.53 g, yield 94%).
34 Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 47f 2 1004331 To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyridin-2-y1)-1,2,3,4-3 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 47e (0.53 g, 0.93 mmol) in N,N-4 dimethylformamide (11 mL) was added sodium acetate (0.17 g, 2.1 mmol), and the mixture was reacted at 120 C
for 8 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added to quench the 6 reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter 7 cake was collected and dried to obtain a yellow solid 47f (0.38 g, yield 78%, HPLC purity: 99.44%).
8 MS (ESL neg. ion) m/z: 518.9 [M-1-1]-;
9 11-1NMR (400 MHz, DMSO-d6) 8 (ppm) 13.31 (s, 1H), 8.46 (d, J= 4.9 Hz, 1H), 8.02 (d, J= 8.6 Hz, 1H), 7.92-7.78 (m, 4H), 7.21 (t, J= 6.1 Hz, 1H), 6.97 (s, 1H), 6.91 (dd, J= 8.7, 2.5 Hz, 1H), 4.19 (t, J= 6.5 Hz, 2H), 3.10 (t, 11 J= 6.4 Hz, 2H).
12 Step 7: Synthesis of 2-(3,5 -dichloro-4-((1 -oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-13 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 47g 14 [00434] 2-(3,5-Dichloro-4-((l-oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 47f (0.38 g, 0.73 mmol) was dissolved in acetic acid (6 mL), 16 then concentrated hydrochloric acid (3 mL) was added. The mixture was reacted at 100 C for 10 hours. The reaction 17 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 18 minutes, filtered, and rinsed with water (10 mL x 3). The filter cake was collected and dried to obtain a yellow solid 19 47g (0.39 g, yield 96%).
Step 8: Synthesis of 2-(3,5-dichloro-4-((1 -oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-21 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,41-1)-dione 47 22 [00435] 2-(3,5 -Dichloro-4-((1 -oxo-2-(pyridin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-23 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 47g (0.39 g, 0.72 mmol) was dissolved in thioglycolic 24 acid (2 mL). The mixture was reacted at 130 C for 7 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated 26 sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 27 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), and the obtained 28 solid was recrystallized at 85 C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give a white solid 47 (0.11 g, yield 29 31%, HPLC purity: 93.27%).
MS (ESL neg. ion) m/z: 494.0 [M-1-1]-;
31 1HNMR (400 MHz, DMSO-d6) 8 (ppm) 12.54 (s, 1H), 8.46 (dd, J= 5.0, 1.9 Hz, 1H), 8.03 (d, J= 8.6 Hz, 1H), 32 7.92-7.77 (m, 4H), 7.74 (s, 1H), 7.25-7.18 (m, 1H), 6.95 (d, J= 2.6 Hz, 1H), 6.88 (dd, J= 8.7, 2.6 Hz, 1H), 4.19 (t, 33 J= 6.3 Hz, 2H), 3.11 (t, J= 6.4 Hz, 2H).

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 Example 48 2-(3,5-dichloro-4-((1-oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-2 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-3,5(2H,411)-dione 48 a ilk o o OH
HN, up IT
411101 n Step 1 _______ N ra11 Step 2 a Step 3 Ste' 4 ri...,..,N

0 N..,....,)" 0 5a 48a 48b 48c CI

r r N
N.,,,,-- 0 0 ?[ 40 0 Step 5 N 101 0 NNO" Step 6 iaN 40 CI 'N' "NH

H -- NI /

48d 48e 48f CN
CI CI
0 0 iii, 0 . _____________________ .
c Step 7 N N a i., N-jt NH .. Step 8 CI W'' N NH
N 0 rY.0 N, 0 110 3 48g COOH 48 4 Step 1:
Synthesis of 6-methoxy-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(211)-one 48a [00436] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 mmol), 4-iodopyridine (3.2 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in toluene (20 mL), and the mixture was reacted at 120 C for 99 hours. The reaction solution was cooled to room temperature, and water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL X 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over ahydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography (petroleum 11 ether/ethyl acetate = 1/1) to give a white solid 48a (1.85 g, yield 86%).
12 Step 2:
Synthesis of 6-hydroxy-24,pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 48b [00437] At 0 C, to a solution of 6-methoxy-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 48a (1.83 g, 7.20 mmol) in dichloromethane (30 mL) was added boron tribromide (1.73 mL, 18.0 mmol) dropwise. Then the mixture was reacted at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water (30 mL). The mixture was stiffed for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and 17 the filter cake was collected and dried to obtain a white solid 48b (1.80 g, yield 100%).

Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 48c [00438] To a solution of 6-hydroxy-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 48b (1.73 g, 7.20 mmol) and 1,2,3-trichloro-5-nitrobenzene (1.79 g, 7.90 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (3.98 g, 28.8 mmol), and the mixture was reacted at 40 C
for 5.5 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain a white solid 48c (2.56 g, 24 yield 83%).
Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 26 48d CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00439] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-2 one 48c (2.16 g, 5.02 mmol) in acetic acid (30 mL) was added iron powder (1.07 g, 19.2 mmol), and the mixture 3 was reacted at 55 C for 4 hours. The reaction solution was cooled to room temperature, iron powder was removed, 4 and water (100 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and 6 concentrated by suction filtration to give a white solid 48d (1.98 g, yield 98%).
7 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyridin-4-y1)-1,2,3,4-8 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetyl)carbamate 48e 9 [00440] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-4-y1)-3,4-dihydroisoquinolin-1(2H)-one 48d (0.50 g, 1.25 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (0.17 g, 2.49 mmol) in 11 water (5 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (0.23 g, 1.5 mmol) was added, 12 and the mixture was reacted for 3 hours. Water (20 mL) was added to the reaction solution. The mixture was stirred 13 for 30 minutes, filtered, washed with water (10 mL x 2), and the filter cake was collected and dried to obtain a 14 yellow solid 48e (0.70 g, yield 99%).
Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-16 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 48f 17 [00441] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyridin-4-y1)-1,2,3,4-18 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetypcarbamate 48e (0.70 g, 1.23 mmol) in N,N-19 dimethylformamide (15 mL) was added sodium acetate (0.25 g, 3.07 mmol), and the mixture was reacted at 120 C
for 8 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added to quench the 21 reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL x 2). The filter 22 cake was collected and dried to obtain a yellow solid 48f (0.62 g, yield 96%, HPLC purity: 97.11%).
23 MS (ESL, neg. ion) m/z: 519.0 [M-11]-;
24 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 8.58 (s, 2H), 8.00 (d, J= 8.6 Hz, 1H), 7.86 (s, 2H), 7.52 (s, 2H), 6.97 (d, J= 2.6 Hz, 1H), 6.91 (dd, J= 8.7, 2.7 Hz, 1H), 4.04 (t, J= 6.5 Hz, 2H), 3.14 (t, J= 6.3 Hz, 2H).
26 Step 7: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-27 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 48g 28 [00442] 2-(3,5-Dichloro-4-((l-oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-29 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 48f (0.52 g, 1.00 mmol) was dissolved in acetic acid (4 mL), then concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 C for 12 hours. The reaction 31 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 32 minutes, filtered, and rinsed with water (10 mL x 3). The filter cake was collected and dried to obtain a yellow solid 33 48g (0.51 g, yield 95%).
34 Step 8: Synthesis of 2-(3,5-dichloro-4-((1 -oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 48 2 [00443] 2-(3,5-Dichloro-4-((l-oxo-2-(pyridin-4-y1)-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-3 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 48g (0.51 g, 0.94 mmol) was dissolved in thioglycolic 4 acid (2 mL). The mixture was reacted at 120 C for 7 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated 6 sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated by suction filtration.
7 The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1), and the 8 obtained solid was recrystallized at 85 C (petroleum ether/ethyl acetate = 1/1, 50 mL) to give a white solid 48 (99 9 mg, yield 21%, HPLC purity: 90.75%).
MS (ESL neg. ion) m/z: 494.0 [M-1-1]-;
11 111 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.54 (s, 1H), 8.83 (d, J= 6.5 Hz, 2H), 8.08 (d, J= 6.7 Hz, 2H), 8.06 12 (d, J= 8.7 Hz, 1H), 7.89 (s, 2H), 7.75 (s, 1H), 6.99 (d, J= 2.6 Hz, 1H), 6.94 (dd, J= 8.7, 2.6 Hz, 1H), 4.20 (t, J=
13 6.3 Hz, 2H), 3.19 (t, J= 6.3 Hz, 2H).
14 Example 49 2-(3,5-dichloro-441-oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-ylloxylpheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-3,5(2H,411)-dione 49 a ra 0 OH
HN11IJQ _______________________ N l'W ____ W. __ .

Step 1 Nila mn 2 Step 4 ..., 0 Step 2 ' tas 1 Step 3 NOõ,, N CI 1 Iv ....== 0 I
5a 49a 49b 49c CI
CI CI
0 di 0 CI 411111kil Nril'NH
NaN tep 5 N N'NY'NjLO Stp 6 NIO 0 N, CI

H
49d 49e 49f CN
CI CI
;& 0 ...-, 0 1, Step 7 Nca 0 N,[ 1 ell CI "'...- N j(NH Step 8 N3,N,ii CI...1---N NH
I ,LT 0 I NLo 17 Step 1: Synthesis of 6-methoxy-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-one 49a 18 [00444] 6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.32 g, 1.7 19 mmol), 3-iodopyridine (2.60 g, 12.7 mmol) and potassium carbonate (2.34 g, 17 mmol) were dissolved in toluene (30 mL), and the mixture was reacted at 120 C for 90 hours. The reaction solution was cooled to room temperature, 21 and water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL x 2).
22 The combined organic layers were washed with saturated sodium chloride (20 mL), dried over ahydrous sodium 23 sulfate and concentrated by suction filtration. The residue was purified by silica gel column chromatography 24 (petroleum ether/ethyl acetate = 2/1) to give a white solid 49a (2.15 g, yield 100%).
Step 2: Synthesis of 6-hydroxy-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-one 49b CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00445] At 0 C, to a solution of 6-methoxy-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(211)-one 49a (2.15 g, 2 8.45 mmol) in dichloromethane (40 mL) was added boron tribromide (2.04 mL, 21.2 mmol) dropwise. Then the 3 mixture was reacted at room temperature for 16 hours. The reaction solution was quenched by pouring into ice water 4 (30 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and the filter cake was collected and dried to obtain a white solid 49b (2.03 g, yield 100%).
6 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-one 49c 7 [00446] To a solution of 6-hydroxy-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(211)-one 49b (2.03 g, 8.45 8 mmol) and 1,2,3-trichloro-5-nitrobenzene (2.10 g, 9.27 mmol) in N,N-dimethylformamide (40 mL) was added 9 potassium carbonate (9.34 g, 67.6 mmol), and the mixture was reacted at 70 C for 5.5 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, 11 filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain a white solid 49c (2.34 g, 12 yield 65%).
13 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-one 14 49d [00447] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-16 one 49c (2.34 g, 5.45 mmol) in acetic acid (30 mL) was added iron powder (1.22 g, 21.8 mmol), and the mixture 17 was reacted at 55 C for 5 hours. The reaction solution was cooled to room temperature, iron powder was removed, 18 and water (50 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic 19 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated by suction filtration to give a white solid 49d (1.75 g, yield 80%).
21 Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyridin-3-y1)-1,2,3,4-22 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 49e 23 [00448] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyridin-3-y1)-3,4-dihydroisoquinolin-1(2H)-24 one 49d (0.50 g, 1.25 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (0.17 g, 2.49 mmol) in water (5 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (0.23 g, 1.5 mmol) was added, 26 and the mixture was reacted for 3 hours. Water (20 mL) was added to the reaction solution. The mixture was stirred 27 for 30 minutes, filtered, washed with water (10 mL x 2), and the filter cake was collected and dried to obtain a 28 yellow solid 49e (0.71 g, yield 100%).
29 Step 6: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 49f 31 [00449] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((1-oxo-2-(pyridin-3-y1)-1,2,3,4-32 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 48e (0.71 g, 1.25 mmol) in N,N-33 dimethylformamide (11 mL) was added sodium acetate (0.25 g, 3.07 mmol), and the mixture was reacted at 120 C
34 for 8 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added to quench the reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL >< 2). The filter CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 cake was collected and dried to obtain a yellow solid 49f (0.62 g, yield 96%, HPLC purity: 97.94%).
2 MS (ESL, neg. ion) m/z: 518.9 [M-11]-;
3 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 8.80 (s, 1H), 8.53 (d, J= 5.0 Hz, 1H), 8.07 (d, J= 8.5 Hz, 111), 7.98 4 (d, J= 8.6 Hz, 1H), 7.86 (s, 2H), 7.65 (dd, J= 8.3, 4.9 Hz, 1H), 6.98 (d, J= 2.6 Hz, 1H), 6.91 (dd, J= 8.6, 2.6 Hz, 1H), 4.04 (t, J= 6.4 Hz, 2H), 3.17 (t, J= 6.2 Hz, 2H).
6 Step 7: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-7 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 49g 8 [00450] 2-(3,5-Dichloro-4-((l-oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-9 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 49f (0.68 g, 1.30 mmol) was dissolved in acetic acid (8 mL), then concentrated hydrochloric acid (4 mL) was added. The mixture was reacted at 100 C for 10 hours. The reaction 11 solution was cooled to room temperature, then water (20 mL) was added.
The reaction mixture was stirred for 10 12 minutes, filtered, and rinsed with water (10 mL x 3). The filter cake was collected and dried to obtain a yellow solid 13 49g (0.53 g, yield 75%).
14 Step 8: Synthesis of 2-(3,5-dichloro-4-((1 -oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl )oxy)ph eny1)-1,2,4-triazin e-3,5 (2H,4H)-di on e 49 16 [00451] 2-(3,5-Dichloro-4-((l-oxo-2-(pyridin-3-y1)-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-17 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 49g (0.53 g, 0.97 mmol) was dissolved in thioglycolic 18 acid (2 mL). The mixture was reacted at 130 C for 4 hours. The reaction solution was cooled to room temperature, 19 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate and concentrated by suction filtration. The 21 residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), and the obtained 22 solid was recrystallized at 85 C (petroleum ether/ethyl acetate = 1/1, 20 mL) to give a white solid 49 (0.26 g, yield 23 53%, HPLC purity: 92.52%).
24 MS (ESL, neg. ion) m/z: 494.0 [M-H];
'H NMR (400 MHz, DMSO-d6) 8 (ppm) 12.54 (s, 1H), 9.01 (dt, J= 8.2, 2.5 Hz, 1H), 8.69 (d, J= 5.5 Hz, 1H), 26 8.47 (t, J= 9.2 Hz, 1H), 8.00 (d, J= 8.6 Hz, 1H), 7.97 (d, J= 2.3 Hz, 1H), 7.89 (s, 2H), 7.74 (d, J= 1.5 Hz, 1H), 27 6.97 (d, J= 2.6 Hz, 1H), 6.91 (dd, J= 8.6, 2.7 Hz, 1H), 4.11 (t, J= 6.2 Hz, 2H), 3.18 (t, J= 6.4 Hz, 2H).
28 Example 50 2-(3,5-dichloro-4-((1-oxo-2-(pyrimidin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-29 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-3,5(2H,411)-dione 50 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 ci r N
. ________________________ - N,i 0 N N
HN
0 0 ' Step 1 CI Step 2 Step 3 ' ____________ LI-,, ;-...-r-.N=1 Step 4 ( :N 0 ,N 0 5a 50a 50b 50c CI
CI CI

,N N IP NH2 Step 5 N N . N,NA
jj, ,,., Step 6 0- -Tr 0 a N NH
a CI N 0- ' LTN 0 H ..-N 0 rV
50d 50e 50f CN
CI CI
Ali 0 Atli 0 AThhi 0 Ail 0 Step 7 N N VI Mr --11, Step 8 c.,,N ,TN NI
NiNH
1 UN' CI N NH
riY. 0 WI CI 411*"

1 50g COOH 50 2 Step 1: Synthesis of 6-methoxy-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(211)-one 50a [00452] 6-Methoxy-3,4-dihydroisoquinolin-1(211)-one 5a (1.50 g, 8.5 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.49 g, 0.85 mmol), cesium carbonate (3.68 g, 17.0 mmol) and 2-iodopyrimidine (3.5 g, 17.0 mmol) were dissolved in 1,4-dioxane (20 mL), and the mixture was reacted at 120 C for 17 hours. The reaction solution was cooled to room temperature, and filtered through a celite pad.
The filter cake was washed with dichloromethane (50 mL) and ethanol (10 mL), the filtrate was concentrated, and the residue was purified by silica 8 gel column chromatography (petroleum ether/ethyl acetate = 1/2) to give a tan solid 50a (1.29 g, yield 90%).
9 Step 2: Synthesis of 6-hydroxy-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 50b [00453] At 0 C, to a solution of 6-methoxy-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(211)-one 50a (1.29 11 g, 5.05 mmol) in dichloromethane (30 mL) was added boron tribromide (0.80 mL, 8.30 mmol) dropwise. Then the mixture was reacted at room temperature for 3 hours. The reaction solution was quenched by pouring into ice water 13 (30 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and 14 the filter cake was collected and dried to obtain a white solid 50b (1.22 g, yield 100%).
Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(211)-one 16 50c [00454] To a solution of 6-hydroxy-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(211)-one 50b (1.22 g, 5.06 mmol) and 1,2,3-trichloro-5-nitrobenzene (1.26 g, 5.56 mmol) in N,N-dimethylformamide (25 mL) was added potassium carbonate (1.40 g, 10.1 mmol), and the mixture was reacted at 70 C
for 6 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain a red solid 50c (1.85 g, 22 yield 85%).

Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 24 50d [00455] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-1(2H)-26 one 50c (1.85 g, 4.29 mmol) in acetic acid (30 mL) was added iron powder (0.96 g, 17.1 mmol), and the mixture CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 was reacted at 55 C for 10 hours. The reaction solution was cooled to room temperature, iron powder was removed, 2 and water (50 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic 3 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and 4 concentrated by suction filtration to give a white solid 50d (1.32 g, yield 77%).
Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyrimidin-2-y1)-1,2,3,4-6 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetyl)carbamate 50e 7 [00456] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(pyrimidin-2-y1)-3,4-dihydroisoquinolin-8 1(211)-one 50d (0.50 g, 1.25 mmol) in acetic acid (10 mL) was added a solution of sodium nitrite (0.17 g, 2.49 9 mmol) in water (5 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (0.23 g, 1.50 mmol) was added, and the mixture was reacted for 3.5 hours. Water (20 mL) was added to the reaction solution. The mixture 11 was stirred for 30 minutes, filtered, washed with water (10 mL x 2), and the filter cake was collected and dried to 12 obtain a yellow solid 50e (0.70 g, yield 99%).
13 Step 6: Synthesis of 2-(3,5 -dichloro-4 -((1 -oxo-2-(pyri midin-2-y1)-1,2,3,4-tetrahydroi soquinol in -6-14 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 50f [00457] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(pyrimidin-2-y1)-1,2,3,4-16 tetrahydroisoquinolin-6-ypoxy)phenyl)hydrazono)acetyl)carbamate 50e (0.70 g, 1.23 mmol) in N,N-17 dimethylformamide (15 mL) was added sodium acetate (0.25 g, 3.1 mmol), and the mixture was reacted at 120 C
18 for 10 hours. The reaction solution was cooled to room temperature, then water (40 mL) was added to quench the 19 reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL >< 2). The filter cake was collected and dried, and the obtained brown solid was recrystallized (ethyl acetate/methanol/petroleum 21 ether = 2/1/2, 50 mL) at 85 C to give a yellow solid 50f (0.46 g, yield 71%, HPLC purity: 97.56%).
22 MS (ESL, neg. ion) m/z: 520.6 [M-11]-;
23 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 8.81 (d, J= 4.8 Hz, 2H), 8.02 (d, J=
8.6 Hz, 1H), 7.87 (s, 2H), 7.35 24 (t, J= 4.9 Hz, 1H), 6.93 (s, 1H), 6.90 (d, J= 8.2 Hz, 1H), 4.10 (t, J=
6.2 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H).
Step 7: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyrimidin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-26 ypoxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 50g 27 1004581 2-(3,5-Dichloro-4-((1 -oxo-2-(pyrimidin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yDoxy)pheny1)-3,5-28 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 50f (0.30 g, 0.57 mmol) was dissolved in acetic acid (4 mL), 29 then concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 C for 12 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred for 10 31 minutes, filtered, and rinsed with water (10 mL x 3). The filter cake was collected and dried to obtain a yellow solid 32 50g (0.30 g, yield 96%).
33 Step 8: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(pyrimidin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-34 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 50 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00459] 2-(3,5-Dichloro-4-((1 -oxo-2-(pyrimidin-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-2 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 50g (0.30 g, 0.55 mmol) was dissolved in thioglycolic 3 acid (1 mL). The mixture was reacted at 90 C for 5 hours. The reaction solution was cooled to room temperature, 4 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated by suction filtration.
6 The residue was separated and purified by pre-HPLC [45%ACN / 55%H20 (0.1%TFA), Phenomenes ACE
7 specification: C18 10 mx50mmx250mm, flow rate: 100 mL/min] to obtain a white solid 50 (60 mg, yield 22%, 8 HPLC purity: 99.63%).
9 MS (ESL, neg. ion) m/z: 495.1 [M-H];
11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 12.53 (s, 1H), 8.82 (d, J= 4.9 Hz, 2H), 8.03 (d, J= 8.7 Hz, 1H), 7.88 11 (s, 2H), 7.74 (s, 1H), 7.36 (t, J= 4.8 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J= 8.7 Hz, 1H), 4.11 (t, J= 6.2 Hz, 2H), 3.13 12 (t, J= 6.2 Hz, 2H).
13 Example 51 2-(3,5-dichloro-4-((2-formy1-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-14 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 51 oc( CI
HON
CI -U1 j NH
N v CI v" NvNI

ON
16 [00460] 243,5 -Dichloro-442 -(hydroxymethyl)-1-oxo-1,2,3,4 -tetrahydroisoquinolin-6-ypoxy)pheny1)-3,5-17 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 39 (30 mg, 0.063 mmol) and pyridinium dichromate (60 mg, 18 0.16 mmol) were dissolved in dichloromethane (6 mL). The mixture was reacted at room temperature for 15 hours.
19 The reaction solution was added with ethyl acetate (10 mL), and ultrasonically oscillated for 10 minutes. The mixture was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column 21 chromatography (petroleum ether/ethyl acetate = 1/3) to obtain a white solid 51(21 mg, yield 70%, HPLC purity:
22 96.92%).
23 MS (ESL neg. ion) m/z: 470.4 [M-1-1]-;
24 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 13.30 (s, 1H), 9.44 (s, 1H), 8.04 (d, J= 8.7 Hz, 111), 7.86 (s, 2H), 7.01 (d, J= 2.1 Hz, 1H), 6.96 (dd, J= 8.6, 2.4 Hz, 1H), 3.88 (t, J= 6.2 Hz, 2H), 3.04 (t, J= 6.1 Hz, 2H).
26 Example 52 2-(3,5-dichloro-4-01-oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-27 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-3,5(2H,411)-dione 52 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 N N OH

HN
õ, Ste Step 2 Step3 o p 1 N N, WI 2 Step 4 0 divil Nw 5a 52a 52b 52c CI
CI CI

JL CS N NH
Step 5 N N ciTIõ . jj Step 6 4 52d 52e 52f CN
CI CI

Step 7 4111I1 N N
CI N NH ci CI N NH
s¨s6 r`lo 1 52g COOH 52 2 Step 1: Synthesis of 6-methoxy-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(211)-one 52a [00461] 6-Methoxy-3,4-dihydroisoquinolin-1(211)-one 5a (1.50 g, 8.5 mmol), ketone iodide (0.48 g, 2.5 mmol), 2-bromothiazole (2.80 g, 17 mmol) and potassium carbonate (2.3 g, 17 mmol) were dissolved in N,N-dimethylformamide (15 mL), and the mixture was reacted at 150 C for 41 hours.
The reaction solution was cooled 6 to room temperature, and water (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (60 mL x 2). The combined organic layers were washed with saturated sodium chloride (20 mL), dried over ahydrous sodium sulfate and concentrated by suction filtration. The residue was purified by silica gel column 9 chromatography (petroleum ether/ethyl acetate = 8/1) to give a white solid 52a (0.86 g, yield 39%).
Step 2: Synthesis of 6-hydroxy-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(211)-one 526 [00462] At 0 C, to a solution of 6-methoxy-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(2B)-one 50a (0.86 g, 3.30 mmol) in dichloromethane (20 mL) was added boron tribromide (0.80 mL, 8.30 mmol) dropwise. Then the mixture was reacted at room temperature for 10 hours. The reaction solution was quenched by pouring into ice water (30 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with water (10 mL), and the filter cake was collected and dried to obtain a white solid 52b (0.80 g, yield 98%).
16 Step 3: Synthesis of 6-(2,6-dichloro-4-nitrophenoxy)-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 52c [00463] To a solution of 6-hydroxy-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(2H)-one 52b (0.80 g, 3.25 mmol) and 1,2,3-trichloro-5-nitrobenzene (0.81 g, 3.57 mmol) in N,N-dimethylformamide (16 mL) was added potassium carbonate (0.90 g, 6.50 mmol), and the mixture was reacted at 40 C
for 17 hours. The reaction solution was cooled to room temperature, then water (30 mL) was added. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL). The filter cake was collected and dried to obtain a white solid 52c (1.06 g, 22 yield 75%).
23 Step 4: Synthesis of 6-(4-amino-2,6-dichlorophenoxy)-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(211)-one 24 52d [00464] To a solution of 6-(2,6-dichloro-4-nitrophenoxy)-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(211)-one 52c (1.06 g, 2.42 mmol) in acetic acid (20 mL) was added iron powder (0.54 g, 9.69 mmol), and the mixture was CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 reacted at 55 C for 8 hours. The reaction solution was cooled to room temperature, iron powder was removed, and 2 water (50 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 2). The combined organic layers 3 were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated 4 by suction filtration to give a white solid 52d (0.74 g, yield 75%).
Step 5: Synthesis of ethyl (2-cyano-2-(2-(3,5-dichloro-441-oxo-2-(thiazol-2-y1)-1,2,3,4-6 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 52e 7 [00465] To a solution of 6-(4-amino-2,6-dichlorophenoxy)-2-(thiazol-2-y1)-3,4-dihydroisoquinolin-1(2H)-8 one 52d (0.40 g, 1.00 mmol) in acetic acid (8 mL) was added a solution of sodium nitrite (0.14 g, 2.00 mmol) in 9 water (4 mL) dropwise at 0 C. After stirring for 15 minutes, N-cyanoacetylurethane (0.19 g, 1.19 mmol) was added, and the mixture was reacted for 3 hours. Water (20 mL) was added to the reaction solution. The mixture was stirred 11 for 30 minutes, filtered, washed with water (10 mL x 2), and the filter cake was collected and dried to obtain a 12 yellow solid 52e (0.56 g, yield 100%).
13 Step 6: Synthesis of 2-(3,5-dichloro-4-((1-oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 52f [00466] To a solution of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((l-oxo-2-(thiazol-2-y1)-1,2,3,4-16 tetrahydroisoquinolin-6-yl)oxy)phenyl)hydrazono)acetyl)carbamate 52e (0.56 g, 0.98 mmol) in N,N-17 dimethylformamide (12 mL) was added sodium acetate (0.18 g, 2.20 mmol), and the mixture was reacted at 120 C
18 for 10 hours. The reaction solution was cooled to room temperature, then water (80 mL) was added to quench the 19 reaction. The reaction mixture was stirred for 10 minutes, filtered, and rinsed with water (10 mL >< 2). The filter cake was collected and dried, and the obtained brown solid was recrystallized (ethyl acetate/petroleum ether = 1/1, 21 100 mL) at 85 C to give a yellow solid 52f (0.45 g, yield 87%, HPLC
purity: 89.52%).
22 MS (ESL, neg. ion) m/z: 525.4 [M-11]-;
23 11-1 NMR (400 MHz, DMSO-d6) 8 (ppm) 8.05 (d, J= 8.6 Hz, 1H), 7.87 (s, 2H), 7.58 (s, 1H), 7.35 (s, 1H), 7.01 24 (s, 1H), 6.95 (d, J= 8.8 Hz, 1H), 4.51 (t, J= 6.5 Hz, 2H), 3.18 (t, J=
6.4 Hz, 2H).
Step 7: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-26 yl)oxy)pheny1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 52g 27 1004671 2-(3,5-Dichloro-4-((l-oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-y1)oxy)pheny1)-3,5-28 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 52f (0.40 g, 0.76 mmol) was dissolved in acetic acid (4 mL), 29 then concentrated hydrochloric acid (2 mL) was added. The mixture was reacted at 100 C for 12 hours. The reaction solution was cooled to room temperature, then water (20 mL) was added. The reaction mixture was stirred for 10 31 minutes, filtered, and rinsed with water (10 mL x 3). The filter cake was collected and dried to obtain a yellow solid 32 52g (0.41 g, yield 100%).
33 Step 8: Synthesis of 2-(3,5-dichloro-4-((l-oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-34 yl)oxy)pheny1)-1,2,4-triazine-3,5(2H,4H)-dione 52 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00468] 2-(3,5-Dichloro-4-((1 -oxo-2-(thiazol-2-y1)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pheny1)-3,5-2 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 52g (0.54 g, 0.99 mmol) was dissolved in thioglycolic 3 acid (2 mL). The mixture was reacted at 130 C for 9 hours. The reaction solution was cooled to room temperature, 4 and ethyl acetate (30 mL) was added. The mixture was washed successively with water (10 mL) and saturated sodium chloride solution (10 mL), then dried over anhydrous sodium sulfate and concentrated by suction filtration.
6 The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1), and the 7 obtained solid was recrystallized at 85 C (ethyl acetate/petroleum ether = 1/1, 20 mL) to give a white solid 52 (0.11 8 g, yield 46%, HPLC purity: 98.09%).
9 MS (ESL, neg. ion) m/z: 500.7 [M-H];
NMR (400 MHz, DMSO-d6) (ppm) 12.53 (s, 1H), 8.05 (d, J= 8.7 Hz, 1H), 7.89 (s, 2H), 7.74 (s, 1H), 11 7.58 (d, J= 3.5 Hz, 1H), 7.35 (d, J= 3.6 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J= 8.6 Hz, 1H), 4.51 (t, J= 6.6 Hz, 2H), 12 3.18 (t, J= 6.4 Hz, 2H).
13 Example 53 2-(5-dichloro-642-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pytidin-14 3-y1)-1,2,4-triazine-3,5(2H,41/)-dione 53 = OBn OBn OH

HL step Stop 2 Step 3 I N =
rt.õ...
NO, 10a 53a 53b 0 53c CI

CI
F air& I 0,,y).
r1 NH

Step 4 lip N =step NH 0 Step 6 NH

0 NHCOOEt 53d 53e CN
53f CN
= C )IL 00 N 0 1,C1 rsj, ____________________ 140 N
Step 7 N NH Step NH
=
0 N,rL0 0 53g COOH 53 16 Step 1: Synthesis of 6-(benzyloxy)-2-(4-fluorobenzy1)-3,4-dihydroisoquinolin-1(2H)-one 53a 17 [00469] To a solution of 6-(benzyloxy)-3,4-dihydroisoquinolin-1(2H)-one 10a (10.0 g, 61.3 mmol) in N,N-18 dimethylformamide (80 mL) was added potassium carbonate (15.0 g, 151 mmol). 4-fluorobenzyl bromide (8.8 mL, 19 74.0 mmol) was added dropwise to the mixture with stirring, then mixture was reacted at 40 C for 10 minutes. The reaction solution was cooled to room temperature, then water (250 mL) was added to quench the reaction. The 21 reaction mixture was filtered. The filter cake was collected and dried, then slurried with (ethyl acetate/petroleum 22 ether = 1/7, 80 mL) to give a white solid 53a (10.6 g, yield 68%) 23 Step 2: Synthesis of 2-(4-fluorobenzy1)-6-hydroxy-3,4-dihydroisoquinolin-1(21-1)-one 53b 24 [00470] 6-(Benzyloxy)-244-fluorobenzy1)-3,4-dihydroisoquinolin-1(211)-one 53a (4.0 g, 11.0 mmol) was dissolved in ethanol (40 mL), and 10% palladium carbon (0.40 g) was added. The reaction mixture was degassed 26 and refilled with hydrogen, and the mixture was hydrogenated (hydrogen balloon) at room temperature for 2 hours.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 The reaction solution was filtered, and the filtrate was collected and concentrated to obtain a white solid 53b (2.9 2 g, yield 97%).
3 Step 3: Synthesis of 6-((3-chloro-5-nitropyridin-2-yl)oxy)-2-(4-fluorobenzy1)-3,4-dihydroisoquinolin-1(211)-4 one 53c [00471] To a solution of 2-(4-fluorobenzy1)-6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one 53b (2.9 g, 11 6 mmol) and 2,3-dichloro-5-nitropyridine (2.5 g, 13 mmol) in /V,N-dimethylformamide (30 mL) was added potassium 7 carbonate (1.6 g, 16 mmol), and the mixture was reacted at 80 C for 3 hours. The reaction solution was cooled to 8 room temperature, then water (60 mL) was added to quench the reaction.
The reaction mixture was stirred for 10 9 minutes, filtered, and the filter cake was collected and dried to obtain a gray solid 53c (4.5 g, yield 98%).
Step 4: Synthesis of 645-amino-3-chloropyridin-2-ypoxy)-2-(4-fluorobenzy1)-3,4-dihydroisoquinolin-11 1(211)-one 53d 12 [00472] To a solution of 643-chloro-5-nitropyridin-2-ypoxy)-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-13 1(211)-one 53c (4.5 g, 11 mmol) in acetic acid (40 mL) was added iron powder (1.5 g, 27 mmol), and the mixture 14 was reacted at 60 C for 5 hours. The reaction solution was cooled to room temperature, then water (100 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (120 mL x 2). The combined organic 16 layers were washed with saturated sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, and 17 concentrated by suction filtration to give black oil 53d (4.0 g, yield 96%).
18 MS (ESL pos. ion) m/z: 431.0 [M+H]t 19 Step 5: Synthesis of ethyl (2-(2-(5-chloro-642-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)pyridin-3-yphydrazono)-2-cyanoacetyl)carbamate 53e 21 [00473] To a solution of 64(5-amino-3-chloropyridin-2-ypoxy)-2-(4-fluorobenzy1)-3,4-dihydroisoquinolin-22 1(211)-one 53d (1.50 g, 3.77 mmol) in acetic acid (25 mL) was added a solution of sodium nitrite (0.52 g, 7.54 23 mmol) in water (10 mL) at 0 C, then N-cyanoacetylurethane (0.88 g, 5.66 mmol) was added. The mixture was 24 reacted for 2 hours. Water (50 mL) was added to quench the reaction. The mixture was stirred for 20 minutes, filtered, and the filter cake was washed with water (10 mL). Then the filter cake was collected and dried to obtain a 26 light yellow solid 53e (2.00 g, yield 96%).
27 Step 6: Synthesis of 2-(5-chloro-6-42-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-28 yl)oxy)pyridin-3-y1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 53f 29 [00474] To a solution of ethyl (2-(2-(5-chloro-6-42-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pyridin-3-yphydrazono)-2-cyanoacetyl)carbamate 53e (2.00 g, 3.62 mmol) in N,N-dimethylformamide (25 31 mL) was added sodium acetate (0.36 g, 4.36 mmol), and the mixture was reacted at 120 C for 6 hours. The reaction 32 solution was cooled to room temperature, and water (20 mL) was added to quench the reaction. The mixture was 33 extracted with ethyl acetate (120 mL x 2). The combined organic layers were washed with saturated sodium chloride 34 solution (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was recrystallized at 80 C (ethanol/ethyl acetate/petroleum ether=1/5/8, 35 mL) to obtain a white solid 53f (0.90 g, yield CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 48%, HPLC purity: 98.11%).
2 MS (ESL, neg. ion) m/z: 517.9 [M-11]-;
3 IHNMR (400 MHz, DMSO-d6) 8 (ppm) 13.29 (s, 1H), 8.25 (s, 2H), 8.00 (d, J= 8.4 Hz, 1H), 7.38 (dd, J= 8.4, 4 5.5 Hz, 2H), 7.30-6.95 (m, 4H), 4.70 (s, 2H), 3.51 (t, J= 6.6 Hz, 2H), 2.98 (t, J= 6.6 Hz, 2H).
Step 7: Synthesis of 2-(5-chloro-6-42-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-6 yl)oxy)pyridin-3-y1)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 53g 7 [00475] 245 -chloro-64(2 -(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pyridin-3-y1)-3,5-8 dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile 53f (0.90 g, 1.73 mmol) was dissolved in acetic acid (16 mL), 9 then concentrated hydrochloric acid (4 mL) was added. The mixture was reacted at 120 C for 12 hours. The reaction solution was cooled to room temperature, then water (45 mL) was added. The reaction mixture was stirred for 10 11 minutes, filtered, and rinsed with water (10 mL x 2). The filter cake was collected and dried to obtain a yellow solid 12 53g (0.80 g, yield 86%).
13 Step 8: Synthesis of 2-(5 -dichloro-6-42 -(4-fluorobenzy1)-1 -oxo-1,2,3,4-tetrahydroisoquinolin-6-14 yl)oxy)pyridin-3-y1)-1,2,4-triazine-3,5(2H,4H)-dione 53 [00476] 245 -Chloro-6-((2-(4-fluorobenzy1)-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-ypoxy)pyridin-3 -y1)-16 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 53g (0.80 g, 1.49 mmol) was dissolved in acetic acid 17 (6 mL), then thiourea (0.57 g, 7.45 mmol) was added. The mixture was reacted at 120 C for 24 hours. The reaction 18 solution was cooled to room temperature, and water (25 mL) was added to quench the reaction. The mixture was 19 extracted with ethyl acetate (40 mL x 2). The combined organic layers were washed successively with water (15 mL x 3) and saturated sodium chloride solution (20 mL x 3), dried over anhydrous sodium sulfate and concentrated 21 by suction filtration. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 22 = 1/1) to give a white solid 53 (0.42 g, yield 57%, HPLC purity:
99.39%).
23 MS (ESL, pos. ion) m/z: 494.0 [M+H];
24 'H NMR (400 MHz, DMSO-d6)8 (ppm) 12.49 (s, 1H), 8.28 (q, J= 2.4 Hz, 2H), 7.99 (d, J= 8.4 Hz, 1H), 7.70 (s, 1H), 7.38 (dd, J= 8.4, 5.5 Hz, 2H), 7.18 (ddd, J= 9.2, 6.8, 2.6 Hz, 4H), 4.70 (s, 2H), 3.51 (t, J= 6.6 Hz, 2H), 26 2.98 (t, J= 6.6 Hz, 211).

28 Example of activity test 29 1. Detection of the agonistic activity of the compound of the present invention to TRa or TRD in the dual luciferase reporter gene experiment 31 [00477] Test materials:
32 HEK293 cells, purchased from ATCC, Cat No. CRL-1573;
33 Fugene HD transfection reaagent, purchased from Promega, Cat No. E231A;
34 DMEM, purchased from Gibco, Cat No. 11995;

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 FBS, purchased from Biosera, Cat No. FB-1280/500;
2 0.25% Trypsin-EDTA, purchased from Gibco, Cat No. 25200-072;
3 Dual-Luciferase Reporter Assay System, purchased from Promega, Cat No. E
1960;
4 96-well plate (round bottom), purchased from Corning, Cat No. 3365.
[00478] Test method:

11EK293 cells were cultured in a full medium of 10% FBS+DMEM. pBind-TRa or pBind-TRI3 (100 ng/a1), pG5Luc (100 ng/ 1), FuGENE HD and Opti-MEM were mixed thoroughly and incubated at room temperature for min, meanwhile HEK293 cells were digested with 0.25% Trypsin-EDTA and resuspended with full medium. The cell density was calculated and adjusted to 500,000 cells/ml, and then the transcription mixture was added to mix with the cell suspension, plated in a 96-well plate (100 L/well), and incubated at 37 C for 24 h. After 24 h, the test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations, and then the compound was diluted with DMEM to a solution containing 10% DMSO. 5 pi, of the compound was placed in a 96-well plate. The final concentration of DMSO was 0.5%, and the compound was co-cultured with the cells for 18 h. After 18 h, the fluorescence signals of firefly and renilla were detected by Dual-Luciferase Reporter Assay System. The firefly fluorescence signal (F) was divided by the renilla fluorescence signal (R) to calculate the F/R ratio, and the Graph 16 Pad Prism software was used to draw the curve and calculate the EC50 value.

[00479] The test results show that the compound of the present invention has obvious agonistic activity and 18 selectivity to TRI3.
19 2. Detection of the binding activity of the compound of the present invention to TRa or TRti in vitro [00480] Test materials LanthaScreen TR-FRET Thyroid Receptor beta Coactivator Assay kit was purchased from Invitrogen, Cat. No.
22 PV4686;

LanthaScreen TR-FRET Thyroid Receptor alfa Coactivator Assay kit was purchased from Invitrogen, Cat. No.
24 PV4687.
[00481] Test method:

The method was experimented with LanthaScreen TR-FRET Thyroid Receptor beta/alfa Coactivator Assay kit. The test compound was dissolved in DMSO and diluted 3 times to a total of 10 concentrations, and then diluted with TR-FRET Coregulator Buffer C in the kit to form a solution containing 2%
DMSO. 10 1.1 of the solution containing 2% DMSO was taken into a 384-well plate, then 5 tit of 4 x TR
beta/alfa-LBD, 5 ILL of a mixture containing 0.4 M fluorescein-SRC2-2 and 8 nM T'b anti-GST antibody were added into each well, mixed thoroughly, and incubated at room temperature for 1 h in the dark. After 1 h, BMG LABTECH's PHERAstar FSX

microplate reader was used to read the fluorescence value (RFU) at excitation 520 urn and emission 495 nm. The FRET ratio was calculated by dividing the emission signal at 520 nm by the emission signal at 495 urn. Graph Pad Prism 5 software was used to draw the curve and calculate the EC50 value.
The in vitro binding activity test results of some of the compounds of the examples of the present invention are shown in Table 1 below.
36 [00482] Table 1 The in vitro binding activity test results of some of the compounds of the examples of the
37 present invention CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 ECso (PM) EC50 ( M) Example No. Example No.
TRa TRf3 TRa TRfl 1 >100 0.26 31d >100 0.034 2 1.47 0.10 31 0.107 <0.0046 3 0.29 0.026 32d >100 0.054 4 0.21 0.018 32 0.181 0.0046 0.074 0.014 33d >100 0.11 7 0.95 0.092 33 0.156 0.017 8 > 100 >10 34 >100 0.021 9 >100 >10 35d >100 0.080 0.206 0.049 35 0.092 <0.0046 12 0.451 0.021 36 0.079 <0.0046 13 0.073 0.013 37 >100 0.043 14 0.226 0.030 38 <0.046 <0.0046 0.176 0.024 39 >100 0.472 16 0.211 0.022 40d >100 0.035 17 0.311 0.034 40 0.179 <0.0046 18 >100 0.192 42 >100 0.016 19 >100 0.501 43 >100 0.031 20d >100 0.534 44 >100 0.0097 >100 0.012 45 >100 0.061 21d >100 0.368 46 >100 0.035 21 >100 0.019 47f >100 0.214 22 0.156 0.011 47 0.161 0.039 23 0.386 0.013 48 0.558 0.065 24 >100 0.075 49f >100 0.769 >100 0.241 49 >100 0.107 26 7.037 0.476 50f 2.620 0.213 27 >100 0.14 50 0.274 0.12 28g >100 0.128 51 >100 0.904 28 >100 0.017 52 0.23 0.016 29 >100 0.091 30d >100 0.065 0.093 0.0062 1 [00483] The test results show that the compound of the present invention has strong binding affinity and 2 selectivity to TRI3.

CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 3. The pharmacokinetic determination of the compound of the present invention 2 [00484] Test purposes: The following method was used to determine the pharmacokinetics of the compound 3 of the present invention.
4 [00485] Test materials:
Experimental reagents and test samples used: Propranolol (internal standard), methanol, ammonium acetate, 6 K2EDTA (potassium ethylenediaminetetraacetic acid), formic acid, acetonitrile, MTBE (methyl tert-butyl ether), 7 KolliphorHS15 (macrogol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are commercially available;
8 SD rats: male, 180-220 g, 7-8 weeks old, purchased from Hunan Slack Experimental Animal Co., Ltd.
9 [00486] Test method:
1. Preparation of the test sample 11 [00487] Each test sample prepared was completely dissolved in a mixture of 5% DMSO + 5% KolliphorHS
12 15 + 90% Saline according solubility property thereof.
13 2. Design of animal experiment Test substance Example compounds of the present invention Intravenous injection/i.v.: n = 3; blood collection time (hours/h): 0.083, 0.25, 0.5, 1, 2, 5, 7, 24 Animal grouping Oral gavage/i.g.: n = 3; blood collection time (hour/h): 0.083, 0.25, 0.5, 1, 2, 5, 7, 24 Intravenous: intravenous administration of hind limbs; Oral: intragastric Drug-delivery way administration.
Blood collection method Tail vein blood sampling Blood volume 200 ¨ 400 pL/time point Anticoagulant K2EDTA
All samples were centrifuged at 10,000 rpm, 4 C for 2 min within 60 min Plasma preparation to separate the plasma. Samples were stored at ¨80 C until assayed. Backup samples are stored for 1 month after analysis.
Fasted for 15 h before administration, free access to water. Eat 4 h after Fasting situation administration.
Test substance: 20% DMSO; Internal standard: Propranolol aqueous Stock solution solution (100 ng/mL) Pharmacokinetic parameters were calculated using a noncompartmental Data processing method by WinNonLin 6.1 software.
14 3. Animal dosage form Group Gender Number Dosage Dosing concentration Dosing volume Intravenous injection i.v. Male 3 1 mg/kg 1 mg/mL 1 mL/kg Gavage i.g. Male 3 5 mg/kg 1 mg/mL 5 mL/kg 4. Solution preparation 16 [00488] (1) Configuration of the stock solution of the test sample: an appropriate amount of the test product 17 was accurately weighed, dissolved in DMSO, diluted to 1 mg/mL with acetonitrile, and shaken well to obtain the 18 stock solution of the test sample, which was stored at ¨20 C for use.
19 [00489] (2) Preparation of internal standard solution: a certain amount of 1 mg/mL Propranolol stock solution was precisely pipetted and diluted to 100 ng/mL with water.
21 5. Sample analysis CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 [00490] Samples were processed by liquid-liquid extraction, chromatographically separated, quantitatively 2 analyzed by multiple reaction ion monitoring (MRM) on a triple quadrupole tandem mass spectrometer, and the 3 concentration of the results was calculated by instrument quantitative software.
4 6. Plasma sample pretreatment [00491] 30 L of plasma sample was precisely pipetted, added with 250 L of internal standard, and vortexed 6 to mix thoroughly. Plasma samples was extracted once with 1 mL of MTBE, centrifuged at 13,000 rpm for 2 min at 7 4 C. 800 L of the supernatant was sucked out, evaporated to dryness in a 96-well nitrogen blower, and the residue 8 was reconstituted with 150 L of methanol/water (v/v = 50/50), vortexed to mix, and injected with an injection 9 volume of 8 L.
7. Preparation of standard sample 11 [00492] An appropriate amount of compound stock solution was precisely pipetted, diluted with acetonitrile 12 to make a series of standard solutions. 20 L of each of the above series of standard solutions was precisely pipetted, 13 added with 180 ILL of blank plasma, vortexed and mixed thoroughly, and prepare plasma samples equivalent to 14 plasma concentrations of 3, 5, 10, 30, 100, 300, 1,000, 3,000, 5,000, and 10,000 ng/mL. The plasma samples were all operated according to the "plasma sample pretreatment", and double-sample analysis was performed for each 16 concentration to establish a standard curve.
17 8. Analysis method 18 [00493] LC/MS/MS method was used to determine the content of the test compound in rat plasma after 19 administration of different compounds.
9. Data processing 21 [00494] Pharmacokinetic parameters were calculated using a noncompartmental method by WinNonLin 6.1 22 software.
23 [00495] The pharmacokinetic test results of some of the compounds of the examples of the present invention 24 are shown in Table 2 below.
[00496] Table 2 The pharmacokinetic test results of some of the compounds of the examples of the present 26 invention Cl Example Dosage C.a. AUCiast AUCTNF T112 Vss F
Route (ml/min/
No. (mg/kg) (ng/m1) (h*ng/m1) (h*ng/m1) (h) (L/kg) (%) kg) 20 iv 1 3990 16300 16400 3.16 1.01 0.251 --ig 5 10400 93700 94400 3.57 -- 115.1 21 iv 1 2760 1020 1020 1.02 16.3 0.308 --ig 5 4730 4160 4180 1.44 --81.9 24 iv 1 4020 3720 3790 1.16 4.39 0.337 --ig 5 7790 21900 223000 2.65 -- -- 117.7 28 iv 1 8400 8730 9640 2.91 1.73 0.246 --ig 5 15500 47000 47000 2.29 --97.6 CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 29 iv 1 4270 48700 56000 8.47 0.297 0.194 --ig 5 10300 159000 236000 14.1 -- -- 66.2 iv 1 3020 18800 22400 9.87 0.744 0.531 --ig 5 8460 110000 124000 7.67 --37 iv 1 4200 20900 21100 3.61 0.789 0.212 --ig 5 12300 121000 122000 3.5 -- -- 116.3 42 iv 1 4340 1860 1960 2.97 8.49 0.658 --ig 5 7700 12700 13200 2.53 -- -- 134.8 iv 1 3410 39800 47700 9.52 0.349 0.26 --ig 5 8120 134000 212000 15.7 -- -- 68.4 iv 1 5430 2110 2150 2.11 7.74 0.4 --ig 5 9030 13900 14300 1.64 -- -- 133.3 iv 1 1780 2460 2510 1.15 6.65 0.57 --ig 5 5320 20300 20600 4.14 -- -- 163.9 46 iv 1 4160 9810 10000 4.24 1.66 0.424 --ig 5 6410 61900 633000 5.93 -- -- 126.5 iv 1 5300 3580 3730 1.14 4.46 0.306 --ig 5 9680 25300 25800 3.63 -- -- 138.3 2 [00497] The test results show that the compounds of the examples of the present invention exhibit excellent 3 pharmacokinetic properties when administered intravenously or orally orally.
4 4. The pharmacodynamic evaluation of the compound of the present invention 5 [00498] Test materials:
6 Western diet: purchased from Research diet, item number: D12079B;
7 MCD diet: purchased from Nantong Trofe Feed Technology Co., Ltd., item number: TP3006R;
8 ALT, AST, ALP, TG, CHO, HDL, LDL and GLU: purchased from Roche, item numbers were: 20764957322, 9 20764949322, 03333701190, 20767107322, 03039773190, 04399803190, 03038866322 and 0440448319, 10 respectively.
11 [00499] 8-Week-old male OB/OB mice: purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.;
12 8-week-old male db/db mice: purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.
13 A. Pharmacodynamic evaluation of compound in Western diet-induced non-alcoholic steatohepatitis 14 (NASH) model of OB/OB mouse 15 [00500] OB/OB mice are leptin gene-deficient mice, and the NASH model of OB/OB mice induced by 16 Western diet is a commonly used NASH in vivo drug efficacy evaluation model. Animals were acclimated to the 17 experiment for 1 week. OB/OB mice were fed with Western diet feed, and the feed was changed three times a week 18 (Monday, Wednesday, Friday). The mice were given drugs at the fifth week after feeding, and administered orally 19 once a day for 6 weeks. The entire experimental period was 10 weeks.
During the experiment, the basic situation of 20 the animals was monitored every day, and the body weight of the mice was recorded once a week. After the CPST Doc: 479957.1 CA Application CPST Ref: 21924/00056 1 experiment, the mice were fasted overnight, and the mice were anesthetized, and the whole blood was collected 2 from the orbit, centrifuged at 4,000 rpm for 10 min at 4 C to obtain serum, which was stored at -80 C. Serum was 3 used for detection ofALT, AST, ALP, TG, CHO, HDL, LDL and GLU. Mice were dissected and livers were removed 4 and weighed. The middle lobe of the liver was stored in an EP tube at -80 C for the determination of the contents of TG and CHO in the liver. The left lobe of the liver was fixed in 10%
formalin, stained with HE, and scored with 6 NAS.
7 B. Pharmacodynamic evaluation of compound in MCD diet-induced non-alcoholic steatohepatitis 8 (NASH) model of db/db mouse 9 [00501] db/db mice are leptin gene-deficient mice, and the NASH model of db/db mice induced by MCD
diet is a commonly used NASH in vivo drug efficacy evaluation model. Animals were acclimated to the experiment 11 for 1 week. db/db mice were fed with MCD diet feed, and the feed was changed three times a week (Monday, 12 Wednesday, Friday). The mice were experimented with drugs while building a model, and administered orally once 13 a day for 8 weeks. The entire experimental period was 8 weeks. During the experiment, the basic situation of the 14 animals was monitored every day, and the body weight of the mice was recorded once a week. After the experiment, the mice were fasted overnight, and the mice were anesthetized, and the whole blood was collected from the orbit, 16 centrifuged at 4,000 rpm for 10 min at 4 C to obtain serum, which was stored at -80 C. Serum was used for detection 17 of ALT, AST, ALP, TG, CHO, HDL, LDL and GLU. Mice were dissected and livers were removed and weighed.
18 The middle lobe of the liver was stored in an EP tube at -80 C for the determination of the contents of TG and CHO
19 in the liver. The left lobe of the liver was fixed in 10% formalin, stained with HE, and scored with NAS.
[00502] The test results show that the compound of the invention can effectively reduce fat accumulation in 21 the liver, relieve inflammation, and improve liver fibrosis.
22 [00503] Reference throughout this specification to "an embodiment", "some embodiments", "one 23 embodiment", "another example", "an example", "a specific example", or "some examples" means that a particular 24 feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as "in 26 some embodiments", "in one embodiment", "in an embodiment", "in another example", "in an example", "in a 27 specific example", or "in some examples" in various places throughout this specification are not necessarily 28 referring to the same embodiment or example of the present disclosure.
Furthermore, the particular features, 29 structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the 31 features of them as long as they are not contradictory to one another.
32 [00504] Although explanatory embodiments have been shown and described, it would be appreciated by 33 those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, 34 alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

CPST Doc: 479957.1

Claims (16)

CA Application CPST Ref: 21924/00056 Claims
1. A compound having Formula (l) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, R3d A
R3a N N'R2 R3b R1 (1) wherein, Y is -0-, -S-, -NR -, -C(=0)-, C1-6 alkylene, C2-6 alkenylene, C2_6 alkynylene, -NR C(=0)- or -C(=0)NR -; wherein the Y is optionally substituted with 1, 2 or 3 Rx;
R is H, deuterium, C.1_6 alkyl, C1-6 haloalkyl, hydroxy C1-6 alkyl, amino C1-6 alkyl or cyano C1-6 alkyl;
each of R3a, R3b, R3C and R3d is independently H, deuterium, F, Cl, Br, l, -CN, -NO2, -COOH, -OH, -NH2, -SH, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy C.1_6 alkyl, amino C1-6 alkyl or cyano C1-6 alkyl;
R1 is H, deuterium, F, Cl, Br, l, -CN, -NO2, -COOH, -OH, -NH2, -SH, Ci_s alkyl, C2-6 alkenyl, C2-6 alkynyl, -C(=0)-C1_6 alkoxy, -C(=0)-C1-6 alkyl, -C(=0)-C1-6 alkylamino, -C(=0)NH2, -S (=0)2-C1-6 alkyl, -S(=0)2-C-1_6 alkylamino, -S(=0)2NH2, C1-6 alkylamino, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, hydroxy C1-6 alkyl, amino C1-6 alkyl, carboxy C1-6 alkyl or cyano C1-6 alkyl;
R2 is H, deuterium, C1-6 alkyl, 02-6 alkenyl, 02-6 alkynyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms;
,Ei ,ui E4 E2 U2 E5'" Z2 E3 63 E6 z ring A is o , o , o or R5 ; wherein, ring A
is optionally substituted with 1, 2 or 3 RY;
r each of El, Ui and Zi is independently -(CR48R41)xc, _ C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2- or -NR8-;
each of E2, U2 and Z2 is independently -CR4bR4d-, -C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2- or CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 each of E3, Es, U3 and Z3 is independently -CR4eR4L, -C(=0)-, -0-, -S-, -S(=0)-, -S(=0)2- or -NW-;
E4 is -CR4g= or -N=; E5 is -CR4h= or -N=;
q is 0, 1, 2 or 3;
each Ra, Rb, Rb and R5 is independently H, deuterium, C1-6 alkyl, C2-6 alkenyl, C2_s alkynyl, C1-6 haloalkyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each Ra, Rb, Rb and R5 is independently and optionally substituted with 1, 2 or 3 RY1;
each R", Rab, R4C, Rad, Rae, R4f, R4g and R" is independently H, deuterium, F, CI, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylamino, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C3-6 cycloalkyl-C14 alkylene, heterocyclyl consisting of 5-6 atoms, (heterocyclyl consisting of 5-6 atoms)-C14 alkylene, Cs_is aryl, C6-113 aryl-C.1_4 alkylene, heteroaryl consisting of 5-6 atoms or (heteroaryl consisting of 5-6 atoms)-Ci4 alkylene, wherein each R4a, Rai), Rac, Rad, Rae, Rar, Rag and R" is independently and optionally substituted with 1, 2 or 3 RY2;
or R" and R4b, together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, or R" and R", together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, or R" and R4f, together with the carbon atoms to which they are attached, form a C3-8 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-8 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY3;
each Rx is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, C1-6 alkyl, Cl_s haloalkyl, C1-6 haloalkoxy, C1_6 alkoxy or C1-6 alkylamino;
each RY is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C1_6 alkoxy or Ci_s alkylamino; or two RY linked on adjacent atoms, together with the atoms to which they are attached, form a C3-3 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-8 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY4;
each RY1 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-C1-6 alkyl, -C(=0)-Ci_s alkoxy, -C(=0)-Ci_6 alkyl, -C(=0)-Ci_6 alkylamino, -C(=0)NH2, -S(=0)2-Ci_s alkyl, -S(=0)2-Ci_6 alkylamino, -S(=0)2NH2, Ci_s alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, Ci_s alkoxy, C1-6 alkylthio, C1-6 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each RY1 is independently and optionally substituted with 1, 2 or 3 Rz;

CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 each Rz, RY2, RY3 and RY4 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -COOH, C1-6 alkyl, C1-6 haloalkyl, 01_6 haloalkoxy, C1-6 alkoxy, C1-6 alkylthio or C1_6 alkylamino.
2. The compound of claim 1, wherein each of R3a, R3b, R3c and R3d is independently H, deuterium, F, CI, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, methylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl or cyanomethyl.
3. The compound of claim 1 or 2, wherein the R1 is H, deuterium, F, CI, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CECH, -C(=0)-OCH3, -C(=0)-OCH2CH3, -C(=0)-OCH(CH3)2, -C(=0)-OCH2CH2CH3, -C(=0)-0(CH2)3CH3, -C(=0)-OCH2CH(CH3)2, -C(=0)-CH3, -C(=0)-CH2CH3, -C(=0)-NHCH3, -C(=0)-N(CH3)2, -C(=0)NH2, -S(=0)2-CH3, -S(=0)2-CH2CH3, -S(=0)2-NHCH3, -S(=0)2NH2, methylamino, ethylamino, methoxy, ethoxy, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, hydroxymethyl, aminomethyl, carboxymethyl or cyanomethyl.
4. The compound of any one of claims 1-3, wherein each Ra, Rb, RC and R5 is independently H, deuterium, Ci_4 alkyl, C2-4 alkenyl, C24 alkynyl, C1-4 haloalkyl, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, C6-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each Ra, Rb, RC and R5 is independently and optionally substituted with 1, 2 or 3 WI.
5. The compound of any one of claims 1-4, wherein each Ra, Rb, RC and R5 is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CECH, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyrazinyl, thiazolyl or oxazolyl, wherein each Ra, Rb, RC
and R5 is independently and optionally substituted with 1, 2 or 3 RY1.
6. The compound of any one of claims 1-5, wherein each Ro is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-C14 alkyl, -C(=0)-Ci_4 alkoxy, -C(=0)-C-14 alkyl, -C(=0)-C1-4 alkylamino, -C(=0)NH2, -S(=0)2-Ci-4 alkyl, -S(=0)2-Ci-4 alkylamino, -S(=0)2NH2, Ci_4 alkyl, C1-4 CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 haloalkyl, C14 haloalkoxy, C14 alkoxy, C14 alkylthio, C14 alkylamino, C3-6 cycloalkyl, heterocyclyl consisting of 5-6 atoms, 06-10 aryl or heteroaryl consisting of 5-6 atoms, wherein each RY1 is independently and optionally substituted with 1, 2 or 3 Rz.
7. The compound of any one of claims 1-6, wherein each RY1 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, -SH, oxo, -0C(=0)-methyl, -0C(=0)-ethyl, -0C(=0)-n-propyl, -0C(=0)-isopropyl, -0C(=0)-n-butyl, -0C(=0)-tert-butyl, -0C(=0)-isobutyl, -C(=0)0-methyl, -C(=0)0-ethyl, -C(=0)0-n-propyl, -C(=0)0-isopropyl, -C(=0)0-n-butyl, -C(=0)0-tert-butyl, -C(=0)0-isobutyl, -C(=0)-methyl, -C(=0)-ethyl, -C(=0)-n-propyl, -C(=0)-isopropyl, -C (=0)-n-butyl, -C(=0)-tert-butyl, -C(=0)-isobutyl, -C(=0)-methylamino, -C(=0)-ethylamino, -C(=0)NH2, -S(=0)2-Ci-3 alkyl, -S(=0)2-C1-3 alkylamino, -S(=0)2NH2, methyl, ethyl, n-propyl, isopropyl, tert-butyl, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, -OCHFCH3, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethylthio, methylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, phenyl, furyl, thienyl, imidazolyl, pyrimidinyl, pyridinyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl or oxazolyl, wherein each RY1 is independently and optionally substituted with 1, 2 or 3 Rz.
8. The compound of any one of claims 1-7, wherein each R4a, R4b, R4C, R4d, R4e, R4f, R4g and R4"
is independently H, deuterium, F, CI, Br, I, -CN, -NO2, -COOH, -OH, -NH2, -SH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH=CH2, -CH2CH=CH2, -CH=CHCH3, -CECH, methoxy, ethoxy, methylamino, ethylamino, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -0CF3, -OCHF2, -OCH2F, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-CH2-, cyclobutyl-CH2-, cyclopentyl-CH2-, cyclohexyl-CH2-, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl-CH2-, pyrazolidinyl-CH2-, tetrahydrofuranyl-CH2-, tetrahydrothiophenyl-CH2-, piperidinyl-CH2-, morpholinyl-CH2-, thiomorpholinyl-CH2-, piperazinyl-CH2-, phenyl, phenyl-CH2-, phenyl-CH2CH2-, furanyl, thienyl, imidazolyl, pyrimidinyl, pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, thiazolyl, oxazolyl, furyl-CH2-, thienyl-CH2-, imidazolyl-CH2-, pyrimidinyl-CH2-, pyridyl-CH2- or pyrrolyl-CH2-, wherein each Ria, R4b, R4C, R4d, R4e, R4f, R49 and Feh is independently and optionally substituted with 1, 2 or 3 RY2;
or Fea and R4b, together with the carbon atoms to which they are attached, form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, or R4C and R4d, together with the carbon atoms to which they are attached, form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, or R4e and R41' , CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 together with the carbon atoms to which they are attached, form a C3-6 carbon ring or a heterocyclyl consisting of 5-6 atoms, wherein each C3-6 carbon ring and heterocyclyl consisting of 5-6 atoms is independently unsubstituted or substituted with 1, 2 or 3 RY3.
9. The compound of any one of claims 1-8, wherein each Rz, RY2, RY3 and RY4 is independently deuterium, F, CI, Br, I, -CN, -OH, -NH2, - COOH, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, -0CF3, -OCHF2, -OCH2F, methoxy, ethoxy or methylamino.
10. The compound of any one of claims 1-10 having one of the following structures:

zi HN N NH N.K NH
o cl CI
y N 0 00 ' CN (1), CN (2), o CI NH N
CI NH

CN (3), CN (4), CI CI
0- o NNH CI CI N NH
O

CN (5), come (6), HN CI NA NH
O rivo CN (7), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 CI o cl N)-NH
--- a N i' NH CI
CN (8), cN (9), a cl o ,,nr1 I NH )] HN,Ti-, CI NANH
0 N -U 0 IVo CN (10), coome (11 ), a cl .o. -,.
(:)õ
---, 1 , ? -J I I I
.,ON , Cl'' 'N NH 11 CI-rsi NH
0 iii 1 !V
0 0 '0 CN (12), CN (13), 91 a N --- --" . IW NKNH
F 0 N NH ' ------z --- cr F)',.-' ''N CI
0 N. ,t, 0 , o N
y -o CN (14), CN (15), cl .0, CI

n CI I
J-NH r 1 1 j, 0 HN
-1 11 -'-- N--- ci -- I
0 ri' 0 II N 'NH

CN (16), 0 N0(17), ?i a r --, , yo, , (:)t 0 CI 2'-N- 'NH HN CI 0 0 NJLNH

T '0 CN (18), CN (19), CI
F s N 0 0 Ny,Lo F 0 0 40 1 CI N'I-LNH
CN (20d), o ri o (20), CI CI
1411 rsi 0 r&I
a W. o NANH
N a 0 N)1-NH
Ny1-0 CI . =-CN (21d), -'--()(21), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 CI
CI

0 (D 0 ,LN
NJ-LNH N
NJLNH
CI CI
0 N 0 N )-, 0(22), '0 (23), a CI
N a N 0 0 N
N
NJLNH

CN (24d), CI

n N)tNH 0 N'-N N 0 CI I

NJLNH
'N '- 1 CI

CN (25d), ) (25), CI
0 0 ,0õ 0 HN
N)-NH x,,õ, N 0 1 ..----..
a -----"NINH

YO ) 0 CN (26), CN (27), CI

0 ,N
N)-LNH
CI

*
CN (28g), F
CI
O
F3C -0,.., I CI
NI,r 1 1 , F3C,...a.õ, 0, -= - = , , 0 CI NI' NH I I I N J-LNH
0 N ,, ..., N / Cl y o CN (29d), 0 (29), CI
D. I CI

411 ao F CI N NH

I I N
Ny,-,0 F CI N NH 0 CN (30d), .L(D (30), CI
CI
..--- .--- 0 .---Nif 0 F-'1µ11r. CI-' 'NIH 0 N 0 NJNH
L
0 N , F CI

CN (31d), (31), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 F CI
F CI
:6, 0 N ,--- CI.õ----,..... N NH F I i!, I
I
0 ri ' 0 F 'Th-r CI -''N jLNI H
N
CN (32d), 0 cl a ,o,_ -.
1 r - 0 0 0 - N , CI N k NH I Ni I I I CI' IIII NNH

0 (33d), o (33), CI
CI
n c 1 ,,1 F3C , ".----r ' - CI' NI' 'NH

I
0 N FaC
y -o CN (34d), o ni Llo (34), CI
F
CI
,C, F r r i 13 0 0 CI '2' 'T'll-r- cl N 'NH N
N )-. NH
0 Tly0 ci a o r (35), CN (35d), CI
CI CI
-, N y- CI 'I\I )I'NH
I
-Me0 m'.¨ CI ¨ N NH 0 tV
0 N ,.-L 0 0 (36), CN
(37d), Cl CI 0 0 0 & ri I ''l NI II -' If Cl N NH
CI' 1111 'N' 'NH 0 1 r"0 (37), o CN (38), a Cl o,,,..-----.
iFi II
JJ, HON,fr CI N 'NH F' If CI' ' N 'NH
0 N , J- 0 y-0 -r 0 CN (39), CN (40d), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 CI
CI F3CO3_.õ.õ,---, .õ----õ,-----,1-.-,õ--0----1- 0 0 N o A .-1-1-.. NH
cl-------!--"N
F CI' N NH 0 N '0 0 N0 (40), CN (41d), CI
CI

0,) F3CO 0 r...rn...Cc , ..,....1 NH

AN H
, N. ,L.,,, I,, - . . ) = ., ¨ Tr 0 11- (41 ), F 0 N CI N 0 N, 0 (42), 1r CI-----N NH

0 N yo F300 01 0 0 1, CN (43d), (43), CI CI

N
CI N NH NI-r-- CI N NH

- (44) 0 N, 0 (45), CI

CI r-- T : .' 12:

ci , 1 ¨ , -L'N NH
0 rl N- T o 0 (46), CN (47f), 9' 01 ,0-i J- , 0 r N 1 , ¨1 A
Iµl- NH rl T''TC ClN NH
0 IL0 (47), NI' O N
'-- 0 (48), CI CI
[ 1 11 0 NI"--- 11 CI' " 'N NH
NA. NH
,- o N ylo N- N
CI
ft,7 CN (49f), 0 N ' (49), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 CI
T
_0 CI

1µ1 , r 1 T1 0 N -N )- 0 Y 1 ci ¨ N NH N N 1 : 1 ,( N 0 N ï cl ¨ N NH

CN (50f), N 0 N 0 (50), ?l o,_ 0 0 CI
0 (I' .1 ,11, 0 ,,,.. ..
, , Cr -N NH N N A
o / y c1 N NH
0 riv CN (51), '-'LO (52), CI

= NI
IÇJ N )t NH
CI
N
CI 0 (53) Br CI

HN
Br N A NH NANH
.......¨..,,,N I
C
0 N ,y-. 0 N
0 y0 CN (54), CN (55), F CI CI

HN1 0 N)-NH HN
[
CIN)-NH
CI
0 N 0 N , CN (56), CN (57), CI CI

I 1 1 i --- --SõNIr-N CI 7'- N ),NH ''S----'N-If --' a CN (68), CN (59), a CI

r ,.1. õ.._ 1 ,N, ..--,...-- HNI
CI '''''' N j1- NH CI NI NH
-2 r -r- -0 ----0 CN (60), CN (61), CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 CI
CI

HN C1I N A NH N,11,NH
HN
CI
0 IV y-L, 0 N y-CN (62), CN (63), cl CI

Fy0NIT,-.õõ--- 0v, ,N"-U,-NH 0 F o -r F N
CI NA,NH

CN (64), --'Lo (65), ni 0 1 F 0 SNI CI N NH CI N NH

o (66), CI CI

Br, 0 0 ii Ni NA,NH CI %PP ---- -fl--.N- a- N "I'NH
0 (:) (68), 0 CI
CI

CI NANH 0 o HN I
NANH
C
0 r0 0 N (71), (70), CI
0 a HN

NANH F N
CI

N A NH

--LO (72), 0 F CI CI
F

0 c 0 NINH NI, 1r _,.
CN%"--'N NH
H CI' 0 N,L 0 o ri0(75), ' 0 (74), F3C
r, ?I
o K

C NJt -N11-1 N. CN (76);

CPST Doc: 479733.1 CA Application CPST Ref: 21924/00056 or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.
11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10, optionally, further comprising any one of pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles or any combination thereof.
12. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 11 in the manufacture of a medicament for stimulating thyroid hormone receptors;
or for preventing, treating or alleviating diseases regulated by thyroid hormone receptors.
13. The use of claim 12, wherein the thyroid hormone receptor is a thyroid hormone í3 receptor.
14. The use of claim 12, wherein the diseases regulated by thyroid hormone receptors are neurodegenerative diseases, nonalcoholic fatty liver diseases, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
15. Use of the compound of any one of claims 1-10 or the pharmaceutical composition of claim 11 in the manufacture of a medicament for preventing, treating or alleviating the following diseases:
neurodegenerative diseases, nonalcoholic fatty liver diseases, liver fibrosis, idiopathic pulmonary fibrosis, atherosclerosis, coronary heart diseases, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes mellitus, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.
16. The use of claim 14 or 15, wherein the nonalcoholic fatty liver disease is nonalcoholic simple fatty liver, nonalcoholic steatohepatitis, cryptogenic cirrhosis associated with nonalcoholic fatty liver disease or primary liver cancer;
the neurodegenerative disease is demyelinating disease, chronic demyelinating disease, leukodystrophy, dementia, ischemic stroke, lacunar stroke, multiple sclerosis, MCT8 deficiency, X-linked adrenal dystrophy, amyotrophic lateral sclerosis or Alzheimer's disease.

CPST Doc. 479733.1
CA3192169A 2020-09-17 2021-09-16 A compound as a thyroid hormone beta receptor agonist and use thereof Pending CA3192169A1 (en)

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